Author: "Boya, Patricia [0000-0003-3045-951X]" - Searchworks@Jio Institute Digital Library Search Results

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1. Aging STINGs: mitophagy at the crossroads of neuroinflammation

Author: Swiss National Science Foundation, Ministerio de Ciencia e Innovación (España), Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio, Boya, Patricia, Swiss National Science Foundation, Ministerio de Ciencia e Innovación (España), Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio, and Boya, Patricia
Abstract: Loss of proteostasis and dysregulated mitochondrial function are part of the traditional hallmarks of aging, and in their last revision impaired macroautophagy and chronic inflammation are also included. Mitophagy is at the intersection of all these processes but whether it undergoes age-associated perturbations was not known. In our recent work, we performed a systematic and systemic analysis of mitolysosome levels in mice and found that, despite the already-known decrease in nonselective macroautophagy, mitophagy remains stable or increases upon aging in all tissues analyzed and is mediated by the PINK1-PRKN-dependent pathway. Further analyses revealed a concomitant increase in mtDNA leakage into the cytosol and activation of the CGAS-STING1 inflammation axis. Notably, both phenomena are also observed in primary fibroblasts from aged human donors. We hypothesized that mitophagy might be selectively upregulated during aging to improve mitochondrial fitness and reduce mtDNA-induced inflammation. Treatment with the mitophagy inducer urolithin A alleviates age-associated neurological decline, including improved synaptic connectivity, cognitive memory and visual function. Supporting our initial hypothesis, urolithin A reduces the levels of cytosolic mtDNA, CGAS-STING1 activation and neuroinflammation. Finally, using an in vitro model of mitochondrial membrane permeabilization we validated that PINK1-PRKN-mediated mitophagy is essential to resolve cytosolic mtDNA-triggered inflammation. These findings open up an integrative approach to tackle aging and increase healthspan via mitophagy induction.
Published: 2024

2. Author Correction: Mitophagy curtails cytosolic mtDNA-dependent activation of cGAS/STING inflammation during aging

Author: Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Villarejo-Zori, Beatriz [0000-0002-5502-4793], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Zapata-Muñoz, Juan [0000-0003-4747-920X], Benítez-Fernández, Rocío [0000-0003-3535-4370], Frutos-Lisón, M.D. [0000-0002-7899-5744], Tomás-Barberán, Francisco Abraham [0000-0002-0790-1739], Espín, Juan Carlos [0000-0002-1068-8692], Area-Gomez, Estela [0000-0002-0962-1570], Gómez-Durán, Aurora [0000-0002-5895-6860], Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio, Villarejo-Zori, Beatriz, Viedma-Poyatos, Álvaro, Zapata-Muñoz, Juan, Benítez-Fernández, Rocío, Frutos-Lisón, M.D., Tomás Barberán, Francisco, Espín de Gea, Juan Carlos, Area-Gomez, Estela, Gómez-Durán, Aurora, Boya, Patricia, Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Villarejo-Zori, Beatriz [0000-0002-5502-4793], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Zapata-Muñoz, Juan [0000-0003-4747-920X], Benítez-Fernández, Rocío [0000-0003-3535-4370], Frutos-Lisón, M.D. [0000-0002-7899-5744], Tomás-Barberán, Francisco Abraham [0000-0002-0790-1739], Espín, Juan Carlos [0000-0002-1068-8692], Area-Gomez, Estela [0000-0002-0962-1570], Gómez-Durán, Aurora [0000-0002-5895-6860], Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio, Villarejo-Zori, Beatriz, Viedma-Poyatos, Álvaro, Zapata-Muñoz, Juan, Benítez-Fernández, Rocío, Frutos-Lisón, M.D., Tomás Barberán, Francisco, Espín de Gea, Juan Carlos, Area-Gomez, Estela, Gómez-Durán, Aurora, and Boya, Patricia
Abstract: The original version of this article contained an error in Fig. 7a. The representative image for ABT-737+QVD+UA (Scr-siRNA) was inadvertently duplicated from the image for Control. The image for ABT-737+QVD+UA (Scr-siRNA) has been replaced with a correct image. This has now been corrected in the HTML and PDF version of this Article.
Published: 2024

3. Mitophagy curtails cytosolic mtDNAdependent activation of cGAS/STING inflammation during aging

Author: Swiss National Science Foundation, Ministerio de Ciencia e Innovación (España), European Commission, Consejo Superior de Investigaciones Científicas (España), Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Villarejo-Zori, Beatriz [0000-0002-5502-4793], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Zapata-Muñoz, Juan [0000-0003-4747-920X], Benítez-Fernández, Rocío [0000-0003-3535-4370], Frutos-Lisón, M.D. [0000-0002-7899-5744], Tomás-Barberán, Francisco Abraham [0000-0002-0790-1739], Espín, Juan Carlos [0000-0002-1068-8692], Area-Gomez, Estela [0000-0002-0962-1570], Gómez-Durán, Aurora [0000-0002-5895-6860], Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio, Villarejo-Zori, Beatriz, Viedma-Poyatos, Álvaro, Zapata-Muñoz, Juan, Benítez-Fernández, Rocío, Frutos-Lisón, M.D., Tomás Barberán, Francisco, Espín de Gea, Juan Carlos, Area-Gomez, Estela, Gómez-Durán, Aurora, Boya, Patricia, Swiss National Science Foundation, Ministerio de Ciencia e Innovación (España), European Commission, Consejo Superior de Investigaciones Científicas (España), Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Villarejo-Zori, Beatriz [0000-0002-5502-4793], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Zapata-Muñoz, Juan [0000-0003-4747-920X], Benítez-Fernández, Rocío [0000-0003-3535-4370], Frutos-Lisón, M.D. [0000-0002-7899-5744], Tomás-Barberán, Francisco Abraham [0000-0002-0790-1739], Espín, Juan Carlos [0000-0002-1068-8692], Area-Gomez, Estela [0000-0002-0962-1570], Gómez-Durán, Aurora [0000-0002-5895-6860], Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio, Villarejo-Zori, Beatriz, Viedma-Poyatos, Álvaro, Zapata-Muñoz, Juan, Benítez-Fernández, Rocío, Frutos-Lisón, M.D., Tomás Barberán, Francisco, Espín de Gea, Juan Carlos, Area-Gomez, Estela, Gómez-Durán, Aurora, and Boya, Patricia
Abstract: Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, the essential selective autophagic degradation of mitochondria, also decreases with age. In our analysis of mitophagy in multiple organs in the mito-QC reporter mouse, mitophagy is either increased or unchanged in old versus young mice. Transcriptomic analysis shows marked upregulation of the type I interferon response in the retina of old mice, which correlates with increased levels of cytosolic mtDNA and activation of the cGAS/STING pathway. Crucially, these same alterations are replicated in primary human fibroblasts from elderly donors. In old mice, pharmacological induction of mitophagy with urolithin A attenuates cGAS/STING activation and ameliorates deterioration of neurological function. These findings point to mitophagy induction as a strategy to decrease age-associated inflammation and increase healthspan.
Published: 2024

4. Mitophagy in the retina: Viewing mitochondrial homeostasis through a new lens

Author: Ministerio de Ciencia e Innovación (España), University of Fribourg, Swiss National Science Foundation, Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Benítez-Fernández, Rocío [0000-0003-3535-4370], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Zapata-Muñoz, Juan [0000-0003-4747-920X], Villarejo-Zori, Beatriz [0000-0002-5502-4793], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio, Benítez-Fernández, Rocío, Viedma-Poyatos, Álvaro, Zapata-Muñoz, Juan, Villarejo-Zori, Beatriz, Gómez-Sintes, Raquel, Boya, Patricia, Ministerio de Ciencia e Innovación (España), University of Fribourg, Swiss National Science Foundation, Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Benítez-Fernández, Rocío [0000-0003-3535-4370], Viedma-Poyatos, Álvaro [0000-0003-4920-6328], Zapata-Muñoz, Juan [0000-0003-4747-920X], Villarejo-Zori, Beatriz [0000-0002-5502-4793], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio, Benítez-Fernández, Rocío, Viedma-Poyatos, Álvaro, Zapata-Muñoz, Juan, Villarejo-Zori, Beatriz, Gómez-Sintes, Raquel, and Boya, Patricia
Abstract: Mitochondrial function is key to support metabolism and homeostasis in the retina, an organ that has one of the highest metabolic rates body-wide and is constantly exposed to photooxidative damage and external stressors. Mitophagy is the selective autophagic degradation of mitochondria within lysosomes, and can be triggered by distinct stimuli such as mitochondrial damage or hypoxia. Here, we review the importance of mitophagy in retinal physiology and pathology. In the developing retina, mitophagy is essential for metabolic reprogramming and differentiation of retina ganglion cells (RGCs). In basal conditions, mitophagy acts as a quality control mechanism, maintaining a healthy mitochondrial pool to meet cellular demands. We summarize the different autophagy- and mitophagy-deficient mouse models described in the literature, and discuss the potential role of mitophagy dysregulation in retinal diseases such as glaucoma, diabetic retinopathy, retinitis pigmentosa, and age-related macular degeneration. Finally, we provide an overview of methods used to monitor mitophagy in vitro, ex vivo, and in vivo. This review highlights the important role of mitophagy in sustaining visual function, and its potential as a putative therapeutic target for retinal and other diseases.
Published: 2023

5. Microglial phagocytosis dysfunction in stroke is driven by energy depletion and induction of autophagy

Author: Ministerio de Ciencia e Innovación (España), Ministerio de Industria y Competitividad (España), Fundación Tatiana Pérez de Guzmán el Bueno, Eusko Jaurlaritza, Beccari, Sol [0000-0003-3959-462X], Sierra-Torre, Virginia [0000-0002-3205-0307], Valero, Jorge [0000-0001-6072-3313], Soria, Federico N. [0000-0003-1229-9663], De Las Heras-Garcia, Laura [0000-0001-9728-8730], Carretero-Guillén, Alejandro [0000-0003-2370-2534], Capetillo-Zarate, Estibaliz [0000-0002-8416-0495], Domercq, María [0000-0002-4918-9276], Ramonet, David [0000-0002-5058-7757], Osman, Ahmed M. [0000-0002-2854-2552], Faust, Travis E. [0000-0002-4567-8435], Touzani, Omar [0000-0002-9513-097X], Pampliega, Olatz [0000-0002-7924-6374], Boya, Patricia [0000-0003-3045-951X], Schafer, Dorothy [0000-0003-2201-6276], Mariño, Guillermo [0000-0003-1960-1677], Canet-Soulas, Emmanuelle [0000-0002-4742-5570], Blomgren, Klas [0000-0002-0476-7271], Plaza-Zabala, Ainhoa [0000-0002-2812-8992], Sierra, Amanda [0000-0001-8415-096X], Beccari, Sol, Sierra-Torre, Virginia, Valero, Jorge, Pereira-Iglesias, Marta, García-Zaballa, Mikel, Soria, Federico N., De Las Heras-Garcia, Laura, Carretero-Guillén, Alejandro, Capetillo-Zarate, Estibaliz, Domercq, María, Huguet, Paloma R., Ramonet, David, Osman, Ahmed M., Han, Wei, Domínguez, Cecilia, Faust, Travis E., Touzani, Omar, Pampliega, Olatz, Boya, Patricia, Schafer, Dorothy, Mariño, Guillermo, Canet-Soulas, Emmanuelle, Blomgren, Klas, Plaza-Zabala, Ainhoa, Sierra, Amanda, Ministerio de Ciencia e Innovación (España), Ministerio de Industria y Competitividad (España), Fundación Tatiana Pérez de Guzmán el Bueno, Eusko Jaurlaritza, Beccari, Sol [0000-0003-3959-462X], Sierra-Torre, Virginia [0000-0002-3205-0307], Valero, Jorge [0000-0001-6072-3313], Soria, Federico N. [0000-0003-1229-9663], De Las Heras-Garcia, Laura [0000-0001-9728-8730], Carretero-Guillén, Alejandro [0000-0003-2370-2534], Capetillo-Zarate, Estibaliz [0000-0002-8416-0495], Domercq, María [0000-0002-4918-9276], Ramonet, David [0000-0002-5058-7757], Osman, Ahmed M. [0000-0002-2854-2552], Faust, Travis E. [0000-0002-4567-8435], Touzani, Omar [0000-0002-9513-097X], Pampliega, Olatz [0000-0002-7924-6374], Boya, Patricia [0000-0003-3045-951X], Schafer, Dorothy [0000-0003-2201-6276], Mariño, Guillermo [0000-0003-1960-1677], Canet-Soulas, Emmanuelle [0000-0002-4742-5570], Blomgren, Klas [0000-0002-0476-7271], Plaza-Zabala, Ainhoa [0000-0002-2812-8992], Sierra, Amanda [0000-0001-8415-096X], Beccari, Sol, Sierra-Torre, Virginia, Valero, Jorge, Pereira-Iglesias, Marta, García-Zaballa, Mikel, Soria, Federico N., De Las Heras-Garcia, Laura, Carretero-Guillén, Alejandro, Capetillo-Zarate, Estibaliz, Domercq, María, Huguet, Paloma R., Ramonet, David, Osman, Ahmed M., Han, Wei, Domínguez, Cecilia, Faust, Travis E., Touzani, Omar, Pampliega, Olatz, Boya, Patricia, Schafer, Dorothy, Mariño, Guillermo, Canet-Soulas, Emmanuelle, Blomgren, Klas, Plaza-Zabala, Ainhoa, and Sierra, Amanda
Abstract: Microglial phagocytosis of apoptotic debris prevents buildup damage of neighbor neurons and inflammatory responses. Whereas microglia are very competent phagocytes under physiological conditions, we report their dysfunction in mouse and preclinical monkey models of stroke (macaques and marmosets) by transient occlusion of the medial cerebral artery (tMCAo). By analyzing recently published bulk and single cell RNA sequencing databases, we show that the phagocytosis dysfunction was not explained by transcriptional changes. In contrast, we demonstrate that the impairment of both engulfment and degradation was related to energy depletion triggered by oxygen and nutrient deprivation (OND), which led to reduced process motility, lysosomal exhaustion, and the induction of a protective macroautophagy/autophagy response in microglia. Basal autophagy, in charge of removing and recycling intracellular elements, was critical to maintain microglial physiology, including survival and phagocytosis, as we determined both in vivo and in vitro using pharmacological and transgenic approaches. Notably, the autophagy inducer rapamycin partially prevented the phagocytosis impairment induced by tMCAo in vivo but not by OND in vitro, where it even had a detrimental effect on microglia, suggesting that modulating microglial autophagy to optimal levels may be a hard to achieve goal. Nonetheless, our results show that pharmacological interventions, acting directly on microglia or indirectly on the brain environment, have the potential to recover phagocytosis efficiency in the diseased brain. We propose that phagocytosis is a therapeutic target yet to be explored in stroke and other brain disorders and provide evidence that it can be modulated in vivo using rapamycin. Abbreviations: AIF1/IBA1: allograft inflammatory factor 1; AMBRA1: autophagy/beclin 1 regulator 1; ATG4B: autophagy related 4B, cysteine peptidase; ATP: adenosine triphosphate; BECN1: beclin 1, autophagy related; CASP3: caspase 3
Published: 2023

6. Identification of a new structural family of SGK1 inhibitors as potential neuroprotective agents

Author: European Commission, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (España), Maestro, Inés [0000-0002-5026-5803], Madruga, Enrique [0000-0002-7012-9737], Boya, Patricia [0000-0003-3045-951X], Martínez, Ana [0000-0002-2707-8110], Maestro, Inés, Madruga, Enrique, Boya, Patricia, Martínez Gil, Ana, European Commission, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (España), Maestro, Inés [0000-0002-5026-5803], Madruga, Enrique [0000-0002-7012-9737], Boya, Patricia [0000-0003-3045-951X], Martínez, Ana [0000-0002-2707-8110], Maestro, Inés, Madruga, Enrique, Boya, Patricia, and Martínez Gil, Ana
Abstract: SGK1 is a serine/threonine kinase involved in several neurodegenerative-related pathways such as apoptosis, neuroinflammation, ionic channel regulation, and autophagy, among others. Despite its potential role as a pharmacological target against this kind of diseases, there are no reported inhibitors able to cross the BBB so far, being a field yet to be explored. In this context, a structure-based virtual screening against this kinase was performed, pointing out the deazapurine moiety as an interesting and easy-to-derivatize scaffold. Moreover, these inhibitors are able to i) exert neuroprotection in an in vitro model of AD and ii) block mitophagy in a PRKN-independent manner, reinforcing the hypothesis of SGK1 inhibitors as neuroprotective chemical tools.
Published: 2023

7. Apoptotic cell death in disease—Current understanding of the NCCD 2023

Author: Associazione Italiana per la Ricerca sul Cancro, Italian Institute for Genomic Medicine, Compagnia di San Paolo, Vitale, Ilio [0000-0002-5918-1841], Pietrocola, Federico [0000-0002-2930-234X], Guilbaud, Emma [0000-0001-5261-1944], Aaronson, Stuart A. [0000-0002-4643-0474], Dieter, Adam [0000-0002-5668-5032], Agostini, Massimiliano [0000-0003-3124-2072], Agostinis, Patrizia [0000-0003-1314-2115], Alnemri, Emad S. [0000-0002-7295-3383], Altucci, Lucia [0000-0002-7312-5387], Amelio, Ivano [0000-0002-9126-5391], Andrews, David W. [0000-0002-9266-7157], Aqeilan, Rami I. [0000-0002-6034-023X], Arama, Eli [0000-0001-5953-0629], Balachandran, Siddharth [0000-0003-2084-1803], Bano, Daniele [0000-0002-9617-5504], Bartek, Jiri [0000-0003-2013-7525], Bazan, Nicolas G. [0000-0002-9243-5444], Bernassola, Francesca [0000-0002-8883-8654], Bertrand, Mathieu J. M. [0000-0001-9000-0626], Bianchi, Marco Emilio [0000-0002-5329-6445], Blander, J. Magarian [0000-0001-9207-1700], Blandino, Giovanni [0000-0002-6970-2241], Blomgren, Klas [0000-0002-0476-7271], Bortner, Carl D. [0000-0002-5444-6628], Bove, Pierluigi [0000-0002-4788-2982], Boya, Patricia [0000-0003-3045-951X], Broz, Petr [0000-0002-2334-7790], Damgaard, Rune Busk [0000-0002-1709-6534], Calin, George A. [0000-0002-7427-0578], Campanella, Michelangelo [0000-0002-6948-4184], Candi, Eleonora [0000-0001-8332-4825], Carbone, Michele [0000-0001-8928-8474], Carmona-Gutierrez, Didac [0000-0001-7548-7771], Cecconi, Francesco [0000-0002-5614-4359], Chen, Guo‑Qiang [0000-0002-7226-1782], Cheng, Emily H. [0000-0002-3595-2648], Chipuk, Jerry E. [0000-0002-1337-842X], Cidlowski, John A. [0000-0003-1420-0516], Ciechanover, Aaron [0000-0001-9184-8944], Ciliberto, Gennaro [0000-0003-2851-8605], Conrad, Marcus [0000-0003-1140-5612], Czabotar, Peter E. [0000-0002-2594-496X], D’Angiolella, Vincenzo [0000-0001-8365-9094], Daugaard, Mads [0000-0001-8383-055X], Dawson, Valina L. [0000-0002-2915-3970], De Maria, Ruggero [0000-0003-2255-0583], Debatin, Klaus-Michael [0000-0002-8397-1886], Deberardinis, Ralph J. [0000-0002-2705-7432], Degterev, Alexei [0000-0002-8240-7132], Del Sal, Giannino [0000-0003-2185-6003], Deshmukh, Mohanish [0000-0002-2597-5862], Di Virgilio, Francesco [0000-0003-3566-1362], Diederich, Marc [0000-0003-0115-4725], Dixon, Scott J. [0000-0001-6230-8199], El-Deiry, Wafik S. [0000-0002-9577-8266], Elrod, John W. [0000-0003-3925-2224], Engeland, Kurt [0000-0003-3525-0440], Fimia, Gian María [0000-0003-4438-3325], Ganini, Carlo [0000-0002-5839-3965], García-Sáez, Ana J. [0000-0002-3894-5945], Garg, Abhishek D. [0000-0002-9976-9922], Garrido, Carmen [0000-0003-1368-1493], Gavathiotis, Evripidis [0000-0001-6319-8331], Ghosh, Sourav [0000-0001-5990-8708], Green, Douglas R. [0000-0002-7332-1417], Gronemeyer, Hinrich [0000-0001-9454-2449}, Häcker, Georg [0000-0003-1058-5746], Hajnóczky, György [0000-0003-3813-2570], Hardwick, J. Marie [0000-0002-4847-2045], Haupt, Ygal [0000-0001-5925-0096], He, Sudan [0000-0002-0846-1210], Heery, David M. [0000-0002-5035-2392], Hengartner, Michael O. [0000-0002-7584-596X], Hetz, Claudio [0000-0003-1120-7966], Hildeman, David A. [0000-0002-0421-8483], Ichijo, Hidenori [0000-0002-5005-6438], Jäättelä, Marja [0000-0001-5950-7111], Janic, Ana [0000-0002-4200-2560], Joseph, Bertrand [0000-0001-5655-9979], Jost, Philipp J. [0000-0003-2454-0362], Kanneganti, Thirumala-Devi [0000-0002-6395-6443], Karin, Michael [0000-0002-2758-6473], Kashkar, Hamid [0000-0003-2796-1429], Kaufmann, Thomas [0000-0001-9906-874X], Kelly, Gemma L. [0000-0002-6533-1201], Kepp, Oliver [0000-0002-6081-9558], Kimchi, Adi [0000-0002-8236-8989], Klionsky, Daniel J. [0000-0002-7828-8118], Kluck, Ruth [0000-0002-7101-1925], Krysko, Dmitri V. [0000-0002-9692-2047], Kulms, Dagmar [0000-0001-6874-0548], Kumar, Sharad [0000-0001-7126-9814], Lavandero, Sergio [0000-0003-4258-1483], Lavrik, Inna N. [0000-0002-9324-309X], Liccardi, Gianmaria [0000-0002-2662-1281], Linkermann, Andreas [0000-0001-6287-9725], Lipton, Stuart A. [0000-0002-3490-1259], Lockshin, Richard A. [0000-0002-4389-4898], López-Otín, Carlos [0000-0001-6964-1904], Luedde, Tom [0000-0002-6288-8821], MacFarlane, Marion [0000-0001-7886-1159], Madeo, Frank [0000-0002-5070-1329], Malorni, Walter [0000-0002-1223-7000], Manic, Gwenola [0000-0003-3759-8029], Marchi, Saverio [0000-0003-2708-1843], Marine, Jean-Christophe [0000-0003-2433-9837], Martin, Seamus J. [0000-0002-8539-3143], Martinou, Jean-Claude [0000-0002-9847-2051], Mastroberardino, Pier G. [0000-0003-2364-4258], Medema, Jan Paul [0000-0003-3045-2924], Mehlen, Patrick [0000-0003-1743-5417], Meier, Pascal [0000-0003-2760-6523], Melino, Gerry [0000-0001-9428-5972], Melino, Sonia [0000-0001-7694-5279], Miao, Edward A. [0000-0001-7295-3490], Moll, Ute M. [0000-0003-1908-7516], Muñoz-Pinedo, Cristina [0000-0002-9120-664X], Murphy, Daniel J. [0000-0002-5538-5468], Niklison-Chirou, Maria Victoria [0000-0002-2147-370X], Novelli, Flavia [0000-0002-3746-7478], Oberst, Andrew [0000-0002-9500-7912], Ofengeim, Dimitry [0000-0003-2348-3642], Opferman, Joseph T. [0000-0002-1147-5621], Oren, Moshe [0000-0003-4311-7172], Pagano, Michele [0000-0003-3210-2442], Panaretakis, Theocharis [0000-0001-5754-6950], Pasparakis, Manolis [0000-0002-9870-0966], Penninger, Josef M. [0000-0002-8194-3777], Pentimalli, Francesca [0000-0003-4740-6801], Pereira, David M. [0000-0003-0384-7592], Pervaiz, Shazib [0000-0002-4738-019X], Peter, Marcus E. [0000-0003-3216-036X], Pinton, Paolo [0000-0001-7108-6508], Porta, Giovanni [0000-0001-5260-2415], Puthalakath, Hamsa [0000-0001-5178-1175], Rabinovich, Gabriel A. [0000-0002-0947-8735], Rajalingam, Krishnaraj [0000-0002-4175-9633], Ravinchandran, Kodi S. [0000-0001-9049-1410], Rehm, Markus [0000-0001-6149-9261], Ricci, Jean-Ehrland [0000-0003-1585-8117], Rizzuto, Rosario [0000-0001-7044-5097], Robinson, Nirmal [0000-0002-7361-9491], Rotblat, Barak [0000-0003-2985-7115], Rothlin, Carla V. [0000-0002-5693-5572], Rubinsztein, David C. [0000-0001-5002-5263], Rufini, Alessandro [0000-0002-5855-655X], Ryan, Kevin M. [0000-0002-1059-9681], Sarosiek, Kristopher A. [0000-0002-4618-5085], Sawa, Akira [0000-0003-1401-3008], Sayan, Emre [0000-0002-5291-1485], Schroder, Kate [0000-0001-9261-3805], Scorrano, Luca [0000-0002-8515-8928], Sesti, Federico [0000-0002-2761-9693], Shi, Yufang [0000-0001-8964-319X], Sica, Giuseppe [0000-0002-7407-0584], Silke, John [0000-0002-7611-5774], Simon, Hans-Uwe [0000-0002-9404-7736], Sistigu, Antonella [0000-0002-2528-1238], Stockwell, Brent R. [0000-0002-3532-3868], Strappazzon, Flavie [0000-0003-0285-7449], Sun, Liming [0000-0002-0136-5605], Sun, Erwei [0000-0001-5664-513X], Szabadkai, G [0000-0002-3006-3577], Tait, Stephen W. G. [0000-0001-7697-132X], Tang, Daolin [0000-0002-1903-6180], Tavernarakis, Nektarios [0000-0002-5253-1466], Turk, Boris [0000-0002-9007-5764], Urbano, Nicoletta [0000-0003-1822-155X], Vandenabeele, Peter [0000-0002-6669-8822], Vanden Berghe, Tom [0000-0002-1633-0974], Vander Heiden, Matthew G. [0000-0002-6702-4192], Vanderluit, Jacqueline L. [0000-0002-4960-920X], Verkhratsky, A. [0000-0003-2592-9898], Villunger, Andreas [0000-0001-8259-4153], Von Karstedt, Silvia [0000-0002-7816-5919], Voss, Anne K. [0000-0002-3853-9381], Vucic, Domagoj [0000-0003-3614-8093], Vuri, Daniela [0000-0001-8693-3845], Wagner, Erwin F. [0000-0001-7872-0196], Walczak, Henning [0000-0002-6312-4591], Wallach, David [0000-0003-2724-9757], Wang, Ruoning [0000-0001-9798-8032], Weber, Achim [0000-0003-0073-3637], Yamazaki, Takahiro [0000-0002-7420-4394], Zakeri, Zahra [0000-0003-4386-8072], Zawacka-Pankau, Joanna E. [0000-0002-7415-2942], Zhivotovsky, Boris [0000-0002-2238-3482], Piacentini, Mauro [0000-0003-2919-1296], Kroemer, Guido [0000-0002-9334-4405], Galluzzi, Lorenzo [0000-0003-2257-8500 ], Vitale, Ilio, Pietrocola, Federico, Guilbaud, Emma, Aaronson, Stuart A., Abrams, John M., Dieter, Adam, Agostini, Massimiliano, Agostinis, Patrizia, Alnemri, Emad S., Altucci, Lucia, Amelio, Ivano, Andrews, David W., Aqeilan, Rami I., Arama, Eli, Baehrecke, Eric H., Balachandran, Siddharth, Bano, Daniele, Barlev, Nickolai A., Bartek, Jiri, Bazan, Nicolas G., Becker, Christoph, Bernassola, Francesca, Bertrand, Mathieu J. M., Bianchi, Marco Emilio, Blagosklonny, Mikhail V., Blander, J. Magarian, Blandino, Giovanni, Blomgren, Klas, Bomer, Christoph, Bortner, Carl D., Bove, Pierluigi, Boya, Patricia, Brenner, Catherine, Broz, Petr, Brunner, T., Damgaard, Rune Busk, Calin, George A., Campanella, Michelangelo, Candi, Eleonora, Carbone, Michele, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K.-M., Chen, Guo‑Qiang, Chen, Quan, Chen, Youhai H., Cheng, Emily H., Chipuk, Jerry E., Cidlowski, John A., Ciechanover, Aaron, Ciliberto, Gennaro, Conrad, Marcus, Cubillos-Ruiz, Juan R., Czabotar, Peter E., D’Angiolella, Vincenzo, Daugaard, Mads, Dawson, Ted M., Dawson, Valina L., De Maria, Ruggero, De Strooper, B., Debatin, Klaus-Michael, Deberardinis, Ralph J., Degterev, Alexei, Del Sal, Giannino, Deshmukh, Mohanish, Di Virgilio, Francesco, Diederich, Marc, Dixon, Scott J., Dynlacht, Brian D., El-Deiry, Wafik S., Elrod, John W., Engeland, Kurt, Fimia, Gian María, Galassi, Claudia, Ganini, Carlo, García-Sáez, Ana J., Garg, Abhishek D., Garrido, Carmen, Gavathiotis, Evripidis, Gerlic, Motti, Ghosh, Sourav, Green, Douglas R., Greene, Lloyd A., Gronemeyer, Hinrich, Häcker, Georg, Hajnóczky, György, Hardwick, J. 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M., Puthalakath, Hamsa, Rabinovich, Gabriel A., Rajalingam, Krishnaraj, Ravinchandran, Kodi S., Rehm, Markus, Ricci, Jean-Ehrland, Rizzuto, Rosario, Robinson, Nirmal, Rodrigues, Cecilia M. P., Rotblat, Barak, Rothlin, Carla V., Rubinsztein, David C., Rudel, Thomas, Rufini, Alessandro, Ryan, Kevin M., Sarosiek, Kristopher A., Sawa, Akira, Sayan, Emre, Schroder, Kate, Scorrano, Luca, Sesti, Federico, Shao, Feng, Shi, Yufang, Sica, Giuseppe, Silke, John, Simon, Hans-Uwe, Sistigu, Antonella, Stephanou, Anastasis, Stockwell, Brent R., Strappazzon, Flavie, Strasser, Andreas, Sun, Liming, Sun, Erwei, Sun, Qiang, Szabadkai, G, Tait, Stephen W. 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[0000-0001-9049-1410], Rehm, Markus [0000-0001-6149-9261], Ricci, Jean-Ehrland [0000-0003-1585-8117], Rizzuto, Rosario [0000-0001-7044-5097], Robinson, Nirmal [0000-0002-7361-9491], Rotblat, Barak [0000-0003-2985-7115], Rothlin, Carla V. [0000-0002-5693-5572], Rubinsztein, David C. [0000-0001-5002-5263], Rufini, Alessandro [0000-0002-5855-655X], Ryan, Kevin M. [0000-0002-1059-9681], Sarosiek, Kristopher A. [0000-0002-4618-5085], Sawa, Akira [0000-0003-1401-3008], Sayan, Emre [0000-0002-5291-1485], Schroder, Kate [0000-0001-9261-3805], Scorrano, Luca [0000-0002-8515-8928], Sesti, Federico [0000-0002-2761-9693], Shi, Yufang [0000-0001-8964-319X], Sica, Giuseppe [0000-0002-7407-0584], Silke, John [0000-0002-7611-5774], Simon, Hans-Uwe [0000-0002-9404-7736], Sistigu, Antonella [0000-0002-2528-1238], Stockwell, Brent R. [0000-0002-3532-3868], Strappazzon, Flavie [0000-0003-0285-7449], Sun, Liming [0000-0002-0136-5605], Sun, Erwei [0000-0001-5664-513X], Szabadkai, G [0000-0002-3006-3577], Tait, Stephen W. G. [0000-0001-7697-132X], Tang, Daolin [0000-0002-1903-6180], Tavernarakis, Nektarios [0000-0002-5253-1466], Turk, Boris [0000-0002-9007-5764], Urbano, Nicoletta [0000-0003-1822-155X], Vandenabeele, Peter [0000-0002-6669-8822], Vanden Berghe, Tom [0000-0002-1633-0974], Vander Heiden, Matthew G. [0000-0002-6702-4192], Vanderluit, Jacqueline L. [0000-0002-4960-920X], Verkhratsky, A. [0000-0003-2592-9898], Villunger, Andreas [0000-0001-8259-4153], Von Karstedt, Silvia [0000-0002-7816-5919], Voss, Anne K. [0000-0002-3853-9381], Vucic, Domagoj [0000-0003-3614-8093], Vuri, Daniela [0000-0001-8693-3845], Wagner, Erwin F. [0000-0001-7872-0196], Walczak, Henning [0000-0002-6312-4591], Wallach, David [0000-0003-2724-9757], Wang, Ruoning [0000-0001-9798-8032], Weber, Achim [0000-0003-0073-3637], Yamazaki, Takahiro [0000-0002-7420-4394], Zakeri, Zahra [0000-0003-4386-8072], Zawacka-Pankau, Joanna E. [0000-0002-7415-2942], Zhivotovsky, Boris [0000-0002-2238-3482], Piacentini, Mauro [0000-0003-2919-1296], Kroemer, Guido [0000-0002-9334-4405], Galluzzi, Lorenzo [0000-0003-2257-8500 ], Vitale, Ilio, Pietrocola, Federico, Guilbaud, Emma, Aaronson, Stuart A., Abrams, John M., Dieter, Adam, Agostini, Massimiliano, Agostinis, Patrizia, Alnemri, Emad S., Altucci, Lucia, Amelio, Ivano, Andrews, David W., Aqeilan, Rami I., Arama, Eli, Baehrecke, Eric H., Balachandran, Siddharth, Bano, Daniele, Barlev, Nickolai A., Bartek, Jiri, Bazan, Nicolas G., Becker, Christoph, Bernassola, Francesca, Bertrand, Mathieu J. M., Bianchi, Marco Emilio, Blagosklonny, Mikhail V., Blander, J. Magarian, Blandino, Giovanni, Blomgren, Klas, Bomer, Christoph, Bortner, Carl D., Bove, Pierluigi, Boya, Patricia, Brenner, Catherine, Broz, Petr, Brunner, T., Damgaard, Rune Busk, Calin, George A., Campanella, Michelangelo, Candi, Eleonora, Carbone, Michele, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K.-M., Chen, Guo‑Qiang, Chen, Quan, Chen, Youhai H., Cheng, Emily H., Chipuk, Jerry E., Cidlowski, John A., Ciechanover, Aaron, Ciliberto, Gennaro, Conrad, Marcus, Cubillos-Ruiz, Juan R., Czabotar, Peter E., D’Angiolella, Vincenzo, Daugaard, Mads, Dawson, Ted M., Dawson, Valina L., De Maria, Ruggero, De Strooper, B., Debatin, Klaus-Michael, Deberardinis, Ralph J., Degterev, Alexei, Del Sal, Giannino, Deshmukh, Mohanish, Di Virgilio, Francesco, Diederich, Marc, Dixon, Scott J., Dynlacht, Brian D., El-Deiry, Wafik S., Elrod, John W., Engeland, Kurt, Fimia, Gian María, Galassi, Claudia, Ganini, Carlo, García-Sáez, Ana J., Garg, Abhishek D., Garrido, Carmen, Gavathiotis, Evripidis, Gerlic, Motti, Ghosh, Sourav, Green, Douglas R., Greene, Lloyd A., Gronemeyer, Hinrich, Häcker, Georg, Hajnóczky, György, Hardwick, J. Marie, Haupt, Ygal, He, Sudan, Heery, David M., Hengartner, Michael O., Hetz, Claudio, Hildeman, David A., Ichijo, Hidenori, Inoue, Satoshi, Jäättelä, Marja, Janic, Ana, Joseph, Bertrand, Jost, Philipp J., Kanneganti, Thirumala-Devi, Karin, Michael, Kashkar, Hamid, Kaufmann, Thomas, Kelly, Gemma L., Kepp, Oliver, Kimchi, Adi, Kitsis, Richard N., Klionsky, Daniel J., Kluck, Ruth, Krysko, Dmitri V., Kulms, Dagmar, Kumar, Sharad, Lavandero, Sergio, Lavrik, Inna N., Lemasters, John J., Liccardi, Gianmaria, Linkermann, Andreas, Lipton, Stuart A., Lockshin, Richard A., López-Otín, Carlos, Luedde, Tom, MacFarlane, Marion, Madeo, Frank, Malorni, Walter, Manic, Gwenola, Mantovani, Roberto, Marchi, Saverio, Marine, Jean-Christophe, Martin, Seamus J., Martinou, Jean-Claude, Mastroberardino, Pier G., Medema, Jan Paul, Mehlen, Patrick, Meier, Pascal, Melino, Gerry, Melino, Sonia, Miao, Edward A., Moll, Ute M., Muñoz-Pinedo, Cristina, Murphy, Daniel J., Niklison-Chirou, Maria Victoria, Novelli, Flavia, Núñez, Gabriel, Oberst, Andrew, Ofengeim, Dimitry, Opferman, Joseph T., Oren, Moshe, Pagano, Michele, Panaretakis, Theocharis, Pasparakis, Manolis, Penninger, Josef M., Pentimalli, Francesca, Pereira, David M., Pervaiz, Shazib, Peter, Marcus E., Pinton, Paolo, Porta, Giovanni, Prehn, Jochen H. M., Puthalakath, Hamsa, Rabinovich, Gabriel A., Rajalingam, Krishnaraj, Ravinchandran, Kodi S., Rehm, Markus, Ricci, Jean-Ehrland, Rizzuto, Rosario, Robinson, Nirmal, Rodrigues, Cecilia M. P., Rotblat, Barak, Rothlin, Carla V., Rubinsztein, David C., Rudel, Thomas, Rufini, Alessandro, Ryan, Kevin M., Sarosiek, Kristopher A., Sawa, Akira, Sayan, Emre, Schroder, Kate, Scorrano, Luca, Sesti, Federico, Shao, Feng, Shi, Yufang, Sica, Giuseppe, Silke, John, Simon, Hans-Uwe, Sistigu, Antonella, Stephanou, Anastasis, Stockwell, Brent R., Strappazzon, Flavie, Strasser, Andreas, Sun, Liming, Sun, Erwei, Sun, Qiang, Szabadkai, G, Tait, Stephen W. G., Tang, Daolin, Tavernarakis, Nektarios, Troy, Carol M., Turk, Boris, Urbano, Nicoletta, Vandenabeele, Peter, Vanden Berghe, Tom, Vander Heiden, Matthew G., Vanderluit, Jacqueline L., Verkhratsky, A., Villunger, Andreas, Von Karstedt, Silvia, Voss, Anne K., Vousden, Karen H., Vucic, Domagoj, Vuri, Daniela, Wagner, Erwin F., Walczak, Henning, Wallach, David, Wang, Ruoning, Wang, Ying, Weber, Achim, Wood, Will, Yamazaki, Takahiro, Yang, Zahra, Zakeri, Zahra, Zawacka-Pankau, Joanna E., Zhang, Lin, Zhang, Haibin, Zhivotovsky, Boris, Zhou, Wenzhao, Piacentini, Mauro, Kroemer, Guido, and Galluzzi, Lorenzo
Abstract: Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.
Published: 2023

8. Apoptosis-inducing factor deficiency induces tissue-specific alterations in autophagy: insights from a preclinical model of mitochondrial disease and exercise training effects

Author: Instituto de Salud Carlos III, European Commission, Fiuza-Luces, Carmen [0000-0001-8131-7007], Delmiro, Aitor [0000-0003-2534-9324], Arenas, Joaquín [0000-0002-2877-5049], Boya, Patricia [0000-0003-3045-951X], Lucia, Alejandro [0000-0002-3025-2060], Morán, María [0000-0001-5408-7189], Laine-Menéndez, Sara, Fernández-de la Torre, Miguel, Fiuza-Luces, Carmen, Delmiro, Aitor, Arenas, Joaquín, Martín, Miguel A., Boya, Patricia, Lucia, Alejandro, Morán, María, Instituto de Salud Carlos III, European Commission, Fiuza-Luces, Carmen [0000-0001-8131-7007], Delmiro, Aitor [0000-0003-2534-9324], Arenas, Joaquín [0000-0002-2877-5049], Boya, Patricia [0000-0003-3045-951X], Lucia, Alejandro [0000-0002-3025-2060], Morán, María [0000-0001-5408-7189], Laine-Menéndez, Sara, Fernández-de la Torre, Miguel, Fiuza-Luces, Carmen, Delmiro, Aitor, Arenas, Joaquín, Martín, Miguel A., Boya, Patricia, Lucia, Alejandro, and Morán, María
Abstract: We analyzed the effects of apoptosis-inducing factor (AIF) deficiency, as well as those of an exercise training intervention on autophagy across tissues (heart, skeletal muscle, cerebellum and brain), that are primarily affected by mitochondrial diseases, using a preclinical model of these conditions, the Harlequin (Hq) mouse. Autophagy markers were analyzed in: (i) 2, 3 and 6 month-old male wild-type (WT) and Hq mice, and (ii) WT and Hq male mice that were allocated to an exercise training or sedentary group. The exercise training started upon onset of the first symptoms of ataxia in Hq mice and lasted for 8 weeks. Higher content of autophagy markers and free amino acids, and lower levels of sarcomeric proteins were found in the skeletal muscle and heart of Hq mice, suggesting increased protein catabolism. Leupeptin-treatment demonstrated normal autophagic flux in the Hq heart and the absence of mitophagy. In the cerebellum and brain, a lower abundance of Beclin 1 and ATG16L was detected, whereas higher levels of the autophagy substrate p62 and LAMP1 levels were observed in the cerebellum. The exercise intervention did not counteract the autophagy alterations found in any of the analyzed tissues. In conclusion, AIF deficiency induces tissue-specific alteration of autophagy in the Hq mouse, with accumulation of autophagy markers and free amino acids in the heart and skeletal muscle, but lower levels of autophagy-related proteins in the cerebellum and brain. Exercise intervention, at least if starting when muscle atrophy and neurological symptoms are already present, is not sufficient to mitigate autophagy perturbations.
Published: 2022

9. Autofagia: reciclarse o morir

Author: Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Boya, Patricia, Jiménez-Loygorri, Juan Ignacio, Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Boya, Patricia, and Jiménez-Loygorri, Juan Ignacio
Published: 2022

10. Ambra1 haploinsufficiency results in metabolic alterations and exacerbates age-associated retinal degeneration

Author: Villarejo-Zori, Beatriz [/0000-0002-5502-4793], Ramírez-Pardo, Ignacio [0000-0003-4873-7274], Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Sierra-Filardi, Elena [0000-0003-4439-2037], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia [0000-0003-3045-951X], Villarejo-Zori, Beatriz, Ramírez-Pardo, Ignacio, Jiménez-Loygorri, Juan Ignacio, Sierra-Filardi, Elena, Alonso-Gil, Sandra, Gómez-Sintes, Raquel, Boya, Patricia, Villarejo-Zori, Beatriz [/0000-0002-5502-4793], Ramírez-Pardo, Ignacio [0000-0003-4873-7274], Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Sierra-Filardi, Elena [0000-0003-4439-2037], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia [0000-0003-3045-951X], Villarejo-Zori, Beatriz, Ramírez-Pardo, Ignacio, Jiménez-Loygorri, Juan Ignacio, Sierra-Filardi, Elena, Alonso-Gil, Sandra, Gómez-Sintes, Raquel, and Boya, Patricia
Abstract: Purpose: Retina is a highly complex and metabolically active tissue that sense the light. Persistent light-induced stimuli lead to constant turnover of the damaged cellular structures by proteostatic mechanisms such as autophagy. During aging there is a gradual decrease of autophagy which compromises retinal homeostasis and visual function. AMBRA1 (autophagy and beclin-1 regulator 1) is a key protein involved in the initiation phase of autophagy pathway. To further determine the importance of autophagy along aging, we will use Ambra1+/gt heterozygous mice, mimicking the decrease of autophagy during the aging process., Methods: We have used young (3 months), middle-aged (12 months) and old (25 months) Ambra1+/+ and Ambra1+/gt mice for this study. Visual function was determined by electroretinographic recordings (ERGs) along aging. Eyes were enucleated for histological porpoises or retinas were isolated for biochemical procedures. Retinal morphology and cellular components were assessed by immunofluorescence techniques on retinal cryosections or flatmounts. mRNA and protein lysates were obtained from isolated retinas. Metabolomic analyses were conducted using mass spectrometry and bioinformatic analysis was performed., Results: Ambra1+/gt retinas display a reduced autophagic flux at young without changes in the retinal integrity and function. However, aged Ambra1+/gt animals show an exacerbated loss of visual function also evidenced by morphological changes as increased gliosis, reduced nuclear density and cone number. Interestingly, we observed increased bipolar cell protrusions that might indicate the loss of synapsis between retinal layers. Partial loss of autophagy results in increased damaged mitochondria evidenced by a reduction in the mitochondrial membrane potential (MMP) in young age, higher oxidative stress at middle-aged and accumulation of mitochondrial mass in old Ambra1+/gt retinas. Finally, by metabolomics, we demonstrate marked metabolic alterations suggestive of defective oxidative metabolism in Ambra1+/gt animals at 1 year of age., Conclusions: Reduced autophagic response in Ambra1 haploinsufficient retinas leads to an exacerbated age-associated declines in retinal function, metabolic alterations and accumulation of damaged mitochondria.
Published: 2022

11. BNIP3L/NIX regulates both mitophagy and pexophagy

Author: Medical Research Council (UK), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Wilhelm, Léa P. [0000-0001-5926-4666], Zapata-Muñoz, Juan [0000-0003-4747-920X], Villarejo-Zori, Beatriz [0000-0002-5502-4793], Toye, Ashley M. [0000-0003-4395-9396], Boya, Patricia [0000-0003-3045-951X], Ganley, Ian G. [0000-0003-1481-9407], Wilhelm, Léa P., Zapata-Muñoz, Juan, Villarejo-Zori, Beatriz, Pellegrin, Stephanie, Martins Freire, Catarina, Toye, Ashley M., Boya, Patricia, Ganley, Ian G., Medical Research Council (UK), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Wilhelm, Léa P. [0000-0001-5926-4666], Zapata-Muñoz, Juan [0000-0003-4747-920X], Villarejo-Zori, Beatriz [0000-0002-5502-4793], Toye, Ashley M. [0000-0003-4395-9396], Boya, Patricia [0000-0003-3045-951X], Ganley, Ian G. [0000-0003-1481-9407], Wilhelm, Léa P., Zapata-Muñoz, Juan, Villarejo-Zori, Beatriz, Pellegrin, Stephanie, Martins Freire, Catarina, Toye, Ashley M., Boya, Patricia, and Ganley, Ian G.
Abstract: Mitochondria and peroxisomes are closely related metabolic organelles, both in terms of origin and in terms of function. Mitochondria and peroxisomes can also be turned over by autophagy, in processes termed mitophagy and pexophagy, respectively. However, despite their close relationship, it is not known if both organelles are turned over under similar conditions, and if so, how this might be coordinated molecularly. Here, we find that multiple selective autophagy pathways are activated upon iron chelation and show that mitophagy and pexophagy occur in a BNIP3L/NIX-dependent manner. We reveal that the outer mitochondrial membrane-anchored NIX protein, previously described as a mitophagy receptor, also independently localises to peroxisomes and drives pexophagy. We show this process happens in vivo, with mouse tissue that lacks NIX having a higher peroxisomal content. We further show that pexophagy is stimulated under the same physiological conditions that activate mitophagy, including cardiomyocyte and erythrocyte differentiation. Taken together, our work uncovers a dual role for NIX, not only in mitophagy but also in pexophagy, thus illustrating the interconnection between selective autophagy pathways.
Published: 2022

12. Ambra1 haploinsufficiency in CD1 mice results in metabolic alterations and exacerbates age-associated retinal degeneration

Author: European Commission, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Ramírez-Pardo, Ignacio [0000-0003-4873-7274], Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Sierra-Filardi, Elena [0000-0003-4439-2037], Mariño, Guillermo [0000-0003-1960-1677], de la Villa, P. [0000-0001-9856-6616], Fitze, Patrick S. [0000-0002-6298-2471], Fuentes, José M. [0000-0001-6910-2089], García-Escudero, Ramón [0000-0001-5640-6542], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia [0000-0003-3045-951X], Ramírez-Pardo, Ignacio, Villarejo-Zori, Beatriz, Jiménez-Loygorri, Juan Ignacio, Sierra-Filardi, Elena, Alonso-Gil, Sandra, Mariño, Guillermo, de la Villa, P., Fitze, Patrick S., Fuentes, José M., García-Escudero, Ramón, Ferrington, Deborah A., Gómez-Sintes, Raquel, Boya, Patricia, European Commission, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Ramírez-Pardo, Ignacio [0000-0003-4873-7274], Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Sierra-Filardi, Elena [0000-0003-4439-2037], Mariño, Guillermo [0000-0003-1960-1677], de la Villa, P. [0000-0001-9856-6616], Fitze, Patrick S. [0000-0002-6298-2471], Fuentes, José M. [0000-0001-6910-2089], García-Escudero, Ramón [0000-0001-5640-6542], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia [0000-0003-3045-951X], Ramírez-Pardo, Ignacio, Villarejo-Zori, Beatriz, Jiménez-Loygorri, Juan Ignacio, Sierra-Filardi, Elena, Alonso-Gil, Sandra, Mariño, Guillermo, de la Villa, P., Fitze, Patrick S., Fuentes, José M., García-Escudero, Ramón, Ferrington, Deborah A., Gómez-Sintes, Raquel, and Boya, Patricia
Abstract: Macroautophagy/autophagy is a key process in the maintenance of cellular homeostasis. The age-dependent decline in retinal autophagy has been associated with photoreceptor degeneration. Retinal dysfunction can also result from damage to the retinal pigment epithelium (RPE), as the RPE-retina constitutes an important metabolic ecosystem that must be finely tuned to preserve visual function. While studies of mice lacking essential autophagy genes have revealed a predisposition to retinal degeneration, the consequences of a moderate reduction in autophagy, similar to that which occurs during physiological aging, remain unclear. Here, we described a retinal phenotype consistent with accelerated aging in mice carrying a haploinsufficiency for Ambra1, a pro-autophagic gene. These mice showed protein aggregation in the retina and RPE, metabolic underperformance, and premature vision loss. Moreover, Ambra1+/gt mice were more prone to retinal degeneration after RPE stress. These findings indicate that autophagy provides crucial support to RPE-retinal metabolism and protects the retina against stress and physiological aging.
Published: 2022

13. Targeting retinoic acid receptor alpha-corepressor interaction activates chaperone-mediated autophagy and protects against retinal degeneration

Author: National Institutes of Health (US), JPB Foundation, Michael J. Fox Foundation for Parkinson's Research, Rainwater Charitable Foundation, Backus Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Gómez-Sintes, Raquel [0000-0003-2854-6964], Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], McCabe, Mericka [0000-0001-6758-2330], Díaz, Antonio [0000-0001-7871-0828], Cotto-Rios, Xiomaris M. [0000-0003-0922-1857], Reynolds, Cara A. [0000-0003-3033-0089], De la Villa, Pedro [0000-0001-9856-6616], Macian, Fernando [0000-0003-2666-035X], Boya, Patricia [0000-0003-3045-951X], Gavathiotis, Evripidis [0000-0001-6319-8331], Cuervo, Ana Maria [0000-0002-0771-700X], Gómez-Sintes, Raquel, Xin, Qisheng, Jiménez-Loygorri, Juan Ignacio, McCabe, Mericka, Díaz, Antonio, Garner, Thomas P., Cotto-Rios, Xiomaris M., Wu, Yang, Dong, Shuxian, Reynolds, Cara A., Patel, Bindi, de la Villa, P., Macian, Fernando, Boya, Patricia, Gavathiotis, Evripidis, Cuervo, Ana Maria, National Institutes of Health (US), JPB Foundation, Michael J. Fox Foundation for Parkinson's Research, Rainwater Charitable Foundation, Backus Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Gómez-Sintes, Raquel [0000-0003-2854-6964], Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], McCabe, Mericka [0000-0001-6758-2330], Díaz, Antonio [0000-0001-7871-0828], Cotto-Rios, Xiomaris M. [0000-0003-0922-1857], Reynolds, Cara A. [0000-0003-3033-0089], De la Villa, Pedro [0000-0001-9856-6616], Macian, Fernando [0000-0003-2666-035X], Boya, Patricia [0000-0003-3045-951X], Gavathiotis, Evripidis [0000-0001-6319-8331], Cuervo, Ana Maria [0000-0002-0771-700X], Gómez-Sintes, Raquel, Xin, Qisheng, Jiménez-Loygorri, Juan Ignacio, McCabe, Mericka, Díaz, Antonio, Garner, Thomas P., Cotto-Rios, Xiomaris M., Wu, Yang, Dong, Shuxian, Reynolds, Cara A., Patel, Bindi, de la Villa, P., Macian, Fernando, Boya, Patricia, Gavathiotis, Evripidis, and Cuervo, Ana Maria
Abstract: Chaperone-mediated autophagy activity, essential in the cellular defense against proteotoxicity, declines with age, and preventing this decline in experimental genetic models has proven beneficial. Here, we have identified the mechanism of action of selective chaperone-mediated autophagy activators previously developed by our group and have leveraged that information to generate orally bioavailable chaperone-mediated autophagy activators with favorable brain exposure. Chaperone-mediated autophagy activating molecules stabilize the interaction between retinoic acid receptor alpha - a known endogenous inhibitor of chaperone-mediated autophagy - and its co-repressor, nuclear receptor corepressor 1, resulting in changes of a discrete subset of the retinoic acid receptor alpha transcriptional program that leads to selective chaperone-mediated autophagy activation. Chaperone-mediated autophagy activators molecules activate this pathway in vivo and ameliorate retinal degeneration in a retinitis pigmentosa mouse model. Our findings reveal a mechanism for pharmacological targeting of chaperone-mediated autophagy activation and suggest a therapeutic strategy for retinal degeneration.
Published: 2021

14. Autophagy induction during stem cell activation plays a key role in salivary gland self-renewal

Author: European Commission, University of Groningen, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Orhon, Idil [0000-0002-0779-8719], Rocchi, Cecilia [0000-0002-1106-6174], Brouwer, Uilke [0000-0003-3646-5830], Boya, Patricia [0000-0003-3045-951X], Coppes, Robe [0000-0001-5503-1064], Reggiori, Fulvio [0000-0003-2652-2686], Orhon, Idil, Rocchi, Cecilia, Villarejo-Zori, Beatriz, Serrano Martínez, Paola, Baanstra, Mirjam, Brouwer, Uilke, Boya, Patricia, Coppes, Robe, Reggiori, Fulvio, European Commission, University of Groningen, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Orhon, Idil [0000-0002-0779-8719], Rocchi, Cecilia [0000-0002-1106-6174], Brouwer, Uilke [0000-0003-3646-5830], Boya, Patricia [0000-0003-3045-951X], Coppes, Robe [0000-0001-5503-1064], Reggiori, Fulvio [0000-0003-2652-2686], Orhon, Idil, Rocchi, Cecilia, Villarejo-Zori, Beatriz, Serrano Martínez, Paola, Baanstra, Mirjam, Brouwer, Uilke, Boya, Patricia, Coppes, Robe, and Reggiori, Fulvio
Abstract: Relatively quiescent tissues like salivary glands (SGs) respond to stimuli such as injury to expand,replace and regenerate. Resident stem/progenitor cells are key in this process because, upon activation, they possess the ability to self-renew. Macroautophagy/autophagy contributes to and regulates differentiation in adult tissues, but an important question is whether this pathway promotes stem cell self-renewal in tissues. We took advantage of a 3D organoid system that allows assessing the self-renewal of mouse SGs stem cells (SGSCs). We found that autophagy in dormant SGSCs has slower flux than self-renewing SGSCs. Importantly, autophagy enhancement upon SGSCs activation is a self-renewal feature in 3D organoid cultures and SGs regenerating in vivo. Accordingly,autophagy ablation in SGSCs inhibits self-renewal whereas pharmacological stimulation promotes self-renewal of mouse and human SGSCs. Thus, autophagy is a key pathway for self-renewal activation in low proliferative adult tissues, and its pharmacological manipulation has the potential to promote tissue regeneration.
Published: 2021

15. Regulation of PRKN-independent mitophagy

Author: Israel Science Foundation, Sagol Institute for Longevity Research, Yeda-Sela Center for Basic Research (Israel), Research Council of Norway, Norwegian Cancer Society, Ministerio de Ciencia, Innovación y Universidades (España), Fundación Tatiana Pérez de Guzmán el Bueno, Comunidad de Madrid, European Commission, Boya, Patricia [0000-0003-3045-951X], Elazar, Zvulun [0000-0002-3231-4464], Simonsen, Anne [0000-0003-4711-7057], Teresak, Petra, Lapao, Ana, Subic, Nemanja, Boya, Patricia, Elazar, Zvulun, Simonsen, Anne, Israel Science Foundation, Sagol Institute for Longevity Research, Yeda-Sela Center for Basic Research (Israel), Research Council of Norway, Norwegian Cancer Society, Ministerio de Ciencia, Innovación y Universidades (España), Fundación Tatiana Pérez de Guzmán el Bueno, Comunidad de Madrid, European Commission, Boya, Patricia [0000-0003-3045-951X], Elazar, Zvulun [0000-0002-3231-4464], Simonsen, Anne [0000-0003-4711-7057], Teresak, Petra, Lapao, Ana, Subic, Nemanja, Boya, Patricia, Elazar, Zvulun, and Simonsen, Anne
Abstract: Mitochondria are dynamic, multifunctional cellular organelles that play a fundamental role in maintaining cellular homeostasis. Keeping the quality of mitochondria in check is of essential importance for functioning and survival of the cells. Selective autophagic clearance of flawed mitochondria, a process termed mitophagy, is one of the most prominent mechanisms through which cells maintain a healthy mitochondrial pool. The best-studied pathway through which mitophagy is exerted is the PINK1-PRKN pathway. However, an increasing number of studies have shown an existence of alternative pathways, where different proteins and lipids are able to recruit autophagic machinery independently of PINK1 and PRKN. The significance of PRKN-independent mitophagy pathways is reflected in various physiological and pathophysiological processes, but many questions regarding the regulation and the interplay between these pathways remain open. Here we review the current knowledge and recent progress made in the field of PRKN-independent mitophagy. Particularly we focus on the regulation of various receptors that participate in targeting impaired mitochondria to autophagosomes independently of PRKN.
Published: 2021

16. Lipid dismantling of lens organelles for clear vision

Author: Boya, Patricia [0000-0003-3045-951X], Boya, Patricia, Boya, Patricia [0000-0003-3045-951X], and Boya, Patricia
Abstract: In the eye, the transparent lens focuses light on the retina. This transparency is achieved during lens development by a newly identified mechanism — whole organelles are destroyed by the degradation of their lipid membranes.
Published: 2021

17. Autophagy and disease: new insights and challenges ahead

Author: Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Fundación Tatiana Pérez de Guzmán el Bueno, Comunidad de Madrid, Boya, Patricia [0000-0003-3045-951X], Boya, Patricia, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Fundación Tatiana Pérez de Guzmán el Bueno, Comunidad de Madrid, Boya, Patricia [0000-0003-3045-951X], and Boya, Patricia
Published: 2021

18. Molecular alterations in sporadic and SOD1-ALS immortalized lymphocytes: towards a personalized therapy

Author: Comunidad de Madrid, European Commission, Instituto de Salud Carlos III, Fundación Española para el Fomento de la Investigación de la Esclerosis Lateral Amiotrófica, Agencia Estatal de Investigación (España), Lastres-Becker, Isabel [0000-0002-4968-2175], Arribas-Blázquez, Marina, Maestro, Inés [0000-0002-5026-5803], Boya, Patricia [0000-0003-3045-951X], Cerdán, Sebastián [0000-0001-9965-0270], García-Redondo, Alberto [0000-0001-7646-386X], Martínez, Ana [0000-0002-2707-8110], Martín-Requero, Ángeles [0000-0002-3416-9440], Lastres-Becker, Isabel, Porras, Gracia, Maestro, Inés, Borrego-Hernández, Daniel, Boya, Patricia, Cerdán, Sebastián, García-Redondo, Alberto, Martínez Gil, Ana, Martín-Requero, Ángeles, Comunidad de Madrid, European Commission, Instituto de Salud Carlos III, Fundación Española para el Fomento de la Investigación de la Esclerosis Lateral Amiotrófica, Agencia Estatal de Investigación (España), Lastres-Becker, Isabel [0000-0002-4968-2175], Arribas-Blázquez, Marina, Maestro, Inés [0000-0002-5026-5803], Boya, Patricia [0000-0003-3045-951X], Cerdán, Sebastián [0000-0001-9965-0270], García-Redondo, Alberto [0000-0001-7646-386X], Martínez, Ana [0000-0002-2707-8110], Martín-Requero, Ángeles [0000-0002-3416-9440], Lastres-Becker, Isabel, Porras, Gracia, Maestro, Inés, Borrego-Hernández, Daniel, Boya, Patricia, Cerdán, Sebastián, García-Redondo, Alberto, Martínez Gil, Ana, and Martín-Requero, Ángeles
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition where motor neurons (MNs) degenerate. Most of the ALS cases are sporadic (sALS), whereas 10% are hereditarily transmitted (fALS), among which mutations are found in the gene that codes for the enzyme superoxide dismutase 1 (SOD1). A central question in ALS field is whether causative mutations display selective alterations not found in sALS patients, or they converge on shared molecular pathways. To identify specific and common mechanisms for designing appropriate therapeutic interventions, we focused on the SOD1-mutated (SOD1-ALS) versus sALS patients. Since ALS pathology involves different cell types other than MNs, we generated lymphoblastoid cell lines (LCLs) from sALS and SOD1-ALS patients and healthy donors and investigated whether they show changes in oxidative stress, mitochondrial dysfunction, metabolic disturbances, the antioxidant NRF2 pathway, inflammatory profile, and autophagic flux. Both oxidative phosphorylation and glycolysis appear to be upregulated in lymphoblasts from sALS and SOD1-ALS. Our results indicate significant differences in NRF2/ARE pathway between sALS and SOD1-ALS lymphoblasts. Furthermore, levels of inflammatory cytokines and autophagic flux discriminate between sALS and SOD1-ALS lymphoblasts. Overall, different molecular mechanisms are involved in sALS and SOD1-ALS patients and thus, personalized medicine should be developed for each case.
Published: 2021

19. New insights into the role of autophagy in retinal and eye diseases

Author: Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Comunidad de Madrid, Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Zapata-Muñoz, Juan [0000-0003-4747-920X], Bell, Katharina [0000-0003-4127-1635], Boya, Patricia [0000-0003-3045-951X], Villarejo-Zori, Beatriz, Jiménez-Loygorri, Juan Ignacio, Zapata-Muñoz, Juan, Bell, Katharina, Boya, Patricia, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Comunidad de Madrid, Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Zapata-Muñoz, Juan [0000-0003-4747-920X], Bell, Katharina [0000-0003-4127-1635], Boya, Patricia [0000-0003-3045-951X], Villarejo-Zori, Beatriz, Jiménez-Loygorri, Juan Ignacio, Zapata-Muñoz, Juan, Bell, Katharina, and Boya, Patricia
Abstract: Autophagy is a fundamental homeostatic pathway that mediates the degradation and recycling of intracellular components. It serves as a key quality control mechanism, especially in non-dividing cells such as neurons. Proteins, lipids, and even whole organelles are engulfed in autophagosomes and delivered to the lysosome for elimination. The retina is a light-sensitive tissue located in the back of the eye that detects and processes visual images. Vision is a highly demanding process, making the eye one of the most metabolically active tissues in the body and photoreceptors display glycolytic metabolism, even in the presence of oxygen. The retina and eye are also exposed to other stressors that can impair their function, including genetic mutations and age-associated changes. Autophagy, among other pathways, is therefore a key process for the preservation of retinal homeostasis. Here, we review the roles of both canonical and non-canonical autophagy in normal retinal function. We discuss the most recent studies investigating the participation of autophagy in eye diseases such as age-related macular degeneration, glaucoma, and diabetic retinopathy and its role protecting photoreceptors in several forms of retinal degeneration. Finally, we consider the therapeutic potential of strategies that target autophagy pathways to treat prevalent retinal and eye diseases.
Published: 2021

20. Towards a better understanding of the neuro-developmental role of autophagy in sickness and in health

Author: Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Comunidad de Madrid, Zapata-Muñoz, Juan [0000-0003-4747-920X], Boya, Patricia [0000-0003-3045-951X], Largo-Barrientos, Pablo [0000-0001-9562-645X], Zapata-Muñoz, Juan, Villarejo-Zori, Beatriz, Largo-Barrientos, Pablo, Boya, Patricia, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Comunidad de Madrid, Zapata-Muñoz, Juan [0000-0003-4747-920X], Boya, Patricia [0000-0003-3045-951X], Largo-Barrientos, Pablo [0000-0001-9562-645X], Zapata-Muñoz, Juan, Villarejo-Zori, Beatriz, Largo-Barrientos, Pablo, and Boya, Patricia
Abstract: Autophagy is a critical cellular process by which biomolecules and cellular organelles are degraded in an orderly manner inside lysosomes. This process is particularly important in neurons: these post-mitotic cells cannot divide or be easily replaced and are therefore especially sensitive to the accumulation of toxic proteins and damaged organelles. Dysregulation of neuronal autophagy is well documented in a range of neurodegenerative diseases. However, growing evidence indicates that autophagy also critically contributes to neurodevelopmental cellular processes, including neurogenesis, maintenance of neural stem cell homeostasis, differentiation, metabolic reprogramming, and synaptic remodelling. These findings implicate autophagy in neurodevelopmental disorders. In this review we discuss the current understanding of the role of autophagy in neurodevelopment and neurodevelopmental disorders, as well as currently available tools and techniques that can be used to further investigate this association.
Published: 2021

21. HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

Author: Pro Retina Foundation, Tistou and Charlotte Kerstan Foundation, German Research Foundation, Swiss National Science Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Samardzija, Marijana [0000-0003-0991-4653], Corna, Andrea [0000-0002-3209-6719], Gómez-Sintes, Raquel [0000-0003-2854-6964], Jarboui, Mohamed Ali [0000-0002-5203-235X], Armento, Angela [0000-0002-6357-1500], Haq, Wadood [0000-0003-0890-9780], Paquet-Durand, Francois [0000-0001-7355-5742], Zrenner, Eberhart [0000-0003-2846-9663], de la Villa, P. [0000-0001-9856-6616], Zeck, Günther [0000-0003-3998-9883], Grimm, Christian [0000-0001-9318-4352], Boya, Patricia [0000-0003-3045-951X], Ueffing, Marius [0000-0003-2209-2113], Trifunovic, Dragana [0000-0003-3168-4196], Samardzija, Marijana, Corna, Andrea, Gómez-Sintes, Raquel, Jarboui, Mohamed Ali, Armento, Angela, Roger, Jerome E., Petridou, Eleni, Haq, Wadood, Paquet-Durand, Francois, Zrenner, Eberhart, de la Villa, P., Zeck, Günther, Grimm, Christian, Boya, Patricia, Ueffing, Marius, Trifunovic, Dragana, Pro Retina Foundation, Tistou and Charlotte Kerstan Foundation, German Research Foundation, Swiss National Science Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Samardzija, Marijana [0000-0003-0991-4653], Corna, Andrea [0000-0002-3209-6719], Gómez-Sintes, Raquel [0000-0003-2854-6964], Jarboui, Mohamed Ali [0000-0002-5203-235X], Armento, Angela [0000-0002-6357-1500], Haq, Wadood [0000-0003-0890-9780], Paquet-Durand, Francois [0000-0001-7355-5742], Zrenner, Eberhart [0000-0003-2846-9663], de la Villa, P. [0000-0001-9856-6616], Zeck, Günther [0000-0003-3998-9883], Grimm, Christian [0000-0001-9318-4352], Boya, Patricia [0000-0003-3045-951X], Ueffing, Marius [0000-0003-2209-2113], Trifunovic, Dragana [0000-0003-3168-4196], Samardzija, Marijana, Corna, Andrea, Gómez-Sintes, Raquel, Jarboui, Mohamed Ali, Armento, Angela, Roger, Jerome E., Petridou, Eleni, Haq, Wadood, Paquet-Durand, Francois, Zrenner, Eberhart, de la Villa, P., Zeck, Günther, Grimm, Christian, Boya, Patricia, Ueffing, Marius, and Trifunovic, Dragana
Abstract: Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of high acuity and color vision and, ultimately to blindness. In RP, a vast number of mutations perturb the structure and function of rod photoreceptors, while cones remain initially unaffected. Extensive rod loss in advanced stages of the disease triggers cone death by a mechanism that is still largely unknown. Here, we show that secondary cone cell death in animal models for RP is associated with increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at late stages of the disease, when the majority of rods have already degenerated, was sufficient to delay cone death and support long-term cone survival in two mouse models for RP, affected by mutations in the phosphodiesterase 6b gene. Moreover, the surviving cones remained light-sensitive, leading to an improvement in visual function. RNA-seq analysis of protected cones demonstrated that HDAC inhibition initiated multi-level protection via regulation of different pro-survival pathways,including MAPK, PI3K-Akt, and autophagy. This study suggests a unique opportunity for targeted pharmacological protection of secondary dying cones by HDAC inhibition and creates hope to maintain vision in RP patients even in advanced disease stages.
Published: 2020

22. Caty Casas (1967-2020)

Author: Boya, Patricia [0000-0003-3045-951X], Boya, Patricia, Boya, Patricia [0000-0003-3045-951X], and Boya, Patricia
Published: 2020

23. Ambra1 and its role during physiological ageing in the retina

Author: Boya, Patricia [0000-0003-3045-951X], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia, Ramírez-Pardo, Ignacio, Villarejo-Zori, Beatriz, Gómez-Sintes, Raquel, Boya, Patricia [0000-0003-3045-951X], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia, Ramírez-Pardo, Ignacio, Villarejo-Zori, Beatriz, and Gómez-Sintes, Raquel
Abstract: Purpose : Ambra1 (activating-molecule in Beclin-1-regulated autophagy) is a protein that regulates the early stages of autophagy initiation. Ambra1 haploinsufficiency is linked to autophagy under several pathological conditions such as Alzheimer Disease, autism or multiple system atrophy. In the retina, there is a decline in the autophagy response upon ageing thus we aimed to test if Ambragt/+ haploinsufficiency might affect retinal ageing., Methods : As Ambra1 homozigous animals are embryonic lethal, we have analised the phenotype of Ambra1gt/+ during aging and compared with Ambra1+/+ litermates. We have assessed retinal morphology and function with ERG in animals up to 24 months as well as compared the metabolic profile using mass spectrometry., Results : Our results show that Ambra1gt/+ display premature death in comparison to control littermates. We also observe symptoms of premature retinal ageing in Ambra1gt/+ mice at 15 months old. This tendency was increased in geriatric animals (>20 months) as Ambra1gt/+ displayed increased inflammatory response and a reduction in the photoreceptor layer thickness. Finally, aged Ambra1gt/+ mice displayed a different metabolic signature indicating a misbalance in the purine metabolism and redox status., Conclusions : This data suggest that autophagy deficiency results in a pro-ageing phenotype and impair retinal homeostasis and metabolism.
Published: 2020

24. Age related retinal Ganglion cell susceptibility in context of autophagy deficiency

Author: Ministerio de Ciencia, Innovación y Universidades (España), European Commission, German Research Foundation, Bell, Katharina [0000-0003-4127-1635], Sierra-Filardi, Elena [0000-0003-4439-2037], Rodríguez-Muela, N. [0000-0003-1065-1870], Schmelter, Carsten [0000-0001-7530-690X], Cecconi, Francesco [0000-0002-5614-4359], Grus, Franz [0000-0003-3978-0967], Boya, Patricia [0000-0003-3045-951X], Bell, Katharina, Rosignol, Ines, Sierra-Filardi, Elena, Rodríguez-Muela, N., Schmelter, Carsten, Cecconi, Francesco, Grus, Franz, Boya, Patricia, Ministerio de Ciencia, Innovación y Universidades (España), European Commission, German Research Foundation, Bell, Katharina [0000-0003-4127-1635], Sierra-Filardi, Elena [0000-0003-4439-2037], Rodríguez-Muela, N. [0000-0003-1065-1870], Schmelter, Carsten [0000-0001-7530-690X], Cecconi, Francesco [0000-0002-5614-4359], Grus, Franz [0000-0003-3978-0967], Boya, Patricia [0000-0003-3045-951X], Bell, Katharina, Rosignol, Ines, Sierra-Filardi, Elena, Rodríguez-Muela, N., Schmelter, Carsten, Cecconi, Francesco, Grus, Franz, and Boya, Patricia
Abstract: Glaucoma is a common age-related disease leading to progressive retinal ganglion cell (RGC) death, visual field defects and vision loss and is the second leading cause of blindness in the elderly worldwide. Mitochondrial dysfunction and impaired autophagy have been linked to glaucoma and induction of autophagy shows neuroprotective effects in glaucoma animal models. We have shown that autophagy decreases with aging in the retina and that autophagy can be neuroprotective for RGCs, but it is currently unknown how aging and autophagy deficiency impact RGCs susceptibility and survival. Using the optic nerve crush model in young and olWelcome@1234d Ambra1 +/gt (autophagy/beclin-1 regulator 1+/gt) mice we analysed the contribution of autophagy deficiency on retinal ganglion cell survival in an age dependent context. Interestingly, old Ambra1 +/gt mice showed decreased RGC survival after optic nerve crush in comparison to old Ambra1 +/+, an effect that was not observed in the young animals. Proteomics and mRNA expression data point towards altered oxidative stress response and mitochondrial alterations in old Ambra1 +/gt animals. This effect is intensified after RGC axonal damage, resulting in reduced oxidative stress response showing decreased levels of Nqo1, as well as failure of Nrf2 induction in the old Ambra1 +/gt. Old Ambra1 +/gt also failed to show increase in Bnip3l and Bnip3 expression after optic nerve crush, a response that is found in the Ambra1 +/+ controls. Primary RGCs derived from Ambra1 +/gt mice show decreased neurite projection and increased levels of apoptosis in comparison to Ambra1 +/+ animals. Our results lead to the conclusion that oxidative stress response pathways are altered in old Ambra1 +/gt mice leading to impaired damage responses upon additional external stress factors.
Published: 2020

25. Serum- and glucocorticoid-induced kinase 1, a new therapeutic target for autophagy modulation in chronic diseases

Author: European Commission, Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Maestro, Inés [0000-0002-5026-5803], Boya, Patricia [0000-0003-3045-951X], Martínez, Ana [0000-0002-2707-8110], Maestro, Inés, Boya, Patricia, Martínez Gil, Ana, European Commission, Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Maestro, Inés [0000-0002-5026-5803], Boya, Patricia [0000-0003-3045-951X], Martínez, Ana [0000-0002-2707-8110], Maestro, Inés, Boya, Patricia, and Martínez Gil, Ana
Abstract: Introduction: Autophagy, a basic cellular degradation pathway essential for survival, is altered both in aging and in many chronic human diseases, including infections, cancer, heart disease, and neurodegeneration. Identifying new therapeutic targets for the control and modulation of autophagy events is therefore of utmost importance in drug discovery. Serum and glucocorticoid activated kinase 1 (SGK1), known for decades for its role in ion channel modulation, is now known to act as a switch for autophagy homeostasis, and has emerged as a novel and important therapeutic target likely to attract considerable research attention in the coming years., Areas covered: In this general review of SGK1 we describe the kinase’s structure and its roles in physiological and pathological contexts. We also discuss small-molecule modulators of SGK1 activity. These modulators are of particular interest to medicinal chemists and pharmacists seeking to develop more potent and selective drug candidates for SGK1, which, despite its key role in autophagy, remains relatively understudied., Expert opinion: The main future challenges in this area are (i) deciphering the role of SGK1 in selective autophagy processes (e.g. mitophagy, lipophagy, and aggrephagy); (ii) identifying selective allosteric modulators of SGK1 with specific biological functions; and (iii) conducting first-in-man clinical studies.
Published: 2020

26. Immunological synapse formation induces mitochondrial clustering and mitophagy in dendritic cells

Author: Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Comunidad de Madrid, Gómez-Cabañas, Laura [0000-0003-3759-4116], López-Cotarelo, Pilar [0000-0003-1578-0110], Boya, Patricia [0000-0003-3045-951X], Gómez-Cabañas, Laura, López-Cotarelo, Pilar, Criado-García, Olga, Murphy, Michael P., Boya, Patricia, Rodríguez-Fernández, José Luis, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Comunidad de Madrid, Gómez-Cabañas, Laura [0000-0003-3759-4116], López-Cotarelo, Pilar [0000-0003-1578-0110], Boya, Patricia [0000-0003-3045-951X], Gómez-Cabañas, Laura, López-Cotarelo, Pilar, Criado-García, Olga, Murphy, Michael P., Boya, Patricia, and Rodríguez-Fernández, José Luis
Abstract: The immunological synapse (IS) is a superstructure formed during T cell activation at the zone of contact between T cells and dendritic cells (DCs). The IS includes specific molecular components in the T cell and DCs sides that may result in different functionality. Most of the studies on the IS have focused on the T cell side of this structure and, in contrast, the information available on the IS of DCs is sparse. Autophagy is a cellular process involved in the clearance of damaged proteins and organelles via lysosomal degradation. Mitophagy is the selective autophagy of damaged mitochondria. In this study, it is shown that IS formation induces clustering of mitochondria in the IS of DCs and partial depolarization of these organelles. At the IS of the DCs also accumulate autophagy and mitophagy markers, even when the kinase complex mTORC1, an inhibitor of the autophagy, is active. Together the results presented indicate that IS formation induces local clustering of mitochondria and mitophagy, which could be a homeostatic mechanism to control the quality of mitochondria in this region. The data underline the complexity of the regulatory mechanisms operating in the IS of DCs.
Published: 2019

27. Acyl-CoA-binding protein is a lipogenic factor that triggers food intake and obesity

Author: Ligue Nationale contre le Cancer (France), Agence Nationale de la Recherche (France), Cancéropôle Île-de-France, Chancellerie des Universités de Paris, European Research Council, Institut National du Cancer (France), Institut Universitaire de France, Fondation Leducq, Swedish Research Council, Austrian Science Fund, Federal Ministry of Science, Research and Economy (Austria), Bravo-San-Pedro, José Manuel [0000-0002-5781-1133], Sica, Valentina [0000-0003-2770-5847], Martins, Isabelle [0000-0003-0885-613X], Pol, Jonathan G. [0000-0002-8355-7562], Loos, Friedemann [0000-0002-5976-5978], Maiuri, Maria Chiara [0000-0001-9760-7674], Niso-Santano, Mireia [0000-0002-6506-422X], Aranda, Fernando [0000-0002-9364-474X], Gorwood, Philip [0000-0003-1845-3676], Ramoz, Nicolas [0000-0002-8070-9938], Cleḿent, Karine [0000-0002-2489-3355], Pelloux, Véronique [0000-0003-3630-4746], Raverdy, Violeta [0000-0001-5754-2028], Denis, Raphaël G.P. [0000-0002-7677-7460], Boya, Patricia [0000-0003-3045-951X], Galluzzi, Lorenzo [0000-0003-2257-8500 ], Madeo, Frank [0000-0002-5070-1329], Cruciani-Guglielmacci, Céline [0000-0002-2562-5360], Tavernarakis, Nektarios [0000-0002-5253-1466 ], López-Otín, Carlos [0000-0001-6964-1904], Magnan, Christophe [0000-0002-7044-2571], Kroemer, Guido [0000-0002-9334-4405], Bravo-San-Pedro, José Manuel, Sica, Valentina, Martins, Isabelle, Pol, Jonathan G., Loos, Friedemann, Maiuri, Maria Chiara, Durand, Sylvère, Bossut, Noélie, Aprahamian, Fanny, Anagnostopoulos, Gerasimos, Niso-Santano, Mireia, Aranda, Fernando, Ramírez-Pardo, Ignacio, Lallement, Justine, Denom, Jessica, Boedec, Erwan, Gorwood, Philip, Ramoz, Nicolas, Cleḿent, Karine, Pelloux, Véronique, Rohia, Alili, Pattou, François, Raverdy, Violeta, Caïazzo, Robert, Denis, Raphaël G.P., Boya, Patricia, Galluzzi, Lorenzo, Madeo, Frank, Migrenne-Li, Stephanie, Cruciani-Guglielmacci, Céline, Tavernarakis, Nektarios, López-Otín, Carlos, Magnan, Christophe, Kroemer, Guido, Ligue Nationale contre le Cancer (France), Agence Nationale de la Recherche (France), Cancéropôle Île-de-France, Chancellerie des Universités de Paris, European Research Council, Institut National du Cancer (France), Institut Universitaire de France, Fondation Leducq, Swedish Research Council, Austrian Science Fund, Federal Ministry of Science, Research and Economy (Austria), Bravo-San-Pedro, José Manuel [0000-0002-5781-1133], Sica, Valentina [0000-0003-2770-5847], Martins, Isabelle [0000-0003-0885-613X], Pol, Jonathan G. [0000-0002-8355-7562], Loos, Friedemann [0000-0002-5976-5978], Maiuri, Maria Chiara [0000-0001-9760-7674], Niso-Santano, Mireia [0000-0002-6506-422X], Aranda, Fernando [0000-0002-9364-474X], Gorwood, Philip [0000-0003-1845-3676], Ramoz, Nicolas [0000-0002-8070-9938], Cleḿent, Karine [0000-0002-2489-3355], Pelloux, Véronique [0000-0003-3630-4746], Raverdy, Violeta [0000-0001-5754-2028], Denis, Raphaël G.P. [0000-0002-7677-7460], Boya, Patricia [0000-0003-3045-951X], Galluzzi, Lorenzo [0000-0003-2257-8500 ], Madeo, Frank [0000-0002-5070-1329], Cruciani-Guglielmacci, Céline [0000-0002-2562-5360], Tavernarakis, Nektarios [0000-0002-5253-1466 ], López-Otín, Carlos [0000-0001-6964-1904], Magnan, Christophe [0000-0002-7044-2571], Kroemer, Guido [0000-0002-9334-4405], Bravo-San-Pedro, José Manuel, Sica, Valentina, Martins, Isabelle, Pol, Jonathan G., Loos, Friedemann, Maiuri, Maria Chiara, Durand, Sylvère, Bossut, Noélie, Aprahamian, Fanny, Anagnostopoulos, Gerasimos, Niso-Santano, Mireia, Aranda, Fernando, Ramírez-Pardo, Ignacio, Lallement, Justine, Denom, Jessica, Boedec, Erwan, Gorwood, Philip, Ramoz, Nicolas, Cleḿent, Karine, Pelloux, Véronique, Rohia, Alili, Pattou, François, Raverdy, Violeta, Caïazzo, Robert, Denis, Raphaël G.P., Boya, Patricia, Galluzzi, Lorenzo, Madeo, Frank, Migrenne-Li, Stephanie, Cruciani-Guglielmacci, Céline, Tavernarakis, Nektarios, López-Otín, Carlos, Magnan, Christophe, and Kroemer, Guido
Abstract: Autophagy facilitates the adaptation to nutritional stress. Here, we show that short-term starvation of cultured cells or mice caused the autophagy-dependent cellular release of acyl-CoA-binding protein (ACBP, also known as diazepam-binding inhibitor, DBI) and consequent ACBP-mediated feedback inhibition of autophagy. Importantly, ACBP levels were elevated in obese patients and reduced in anorexia nervosa. In mice, systemic injection of ACBP protein inhibited autophagy, induced lipogenesis, reduced glycemia, and stimulated appetite as well as weight gain. We designed three approaches to neutralize ACBP, namely, inducible whole-body knockout, systemic administration of neutralizing antibodies, and induction of antiACBP autoantibodies in mice. ACBP neutralization enhanced autophagy, stimulated fatty acid oxidation, inhibited appetite, reduced weight gain in the context of a high-fat diet or leptin deficiency, and accelerated weight loss in response to dietary changes. In conclusion, neutralization of ACBP might constitute a strategy for treating obesity and its co-morbidities.
Published: 2019

28. A comparative map of macroautophagy and mitophagy in the vertebrate eye

Author: Medical Research Council (UK), Ministerio de Ciencia, Innovación y Universidades (España), Fundación Tatiana Pérez de Guzmán el Bueno, Prescott, Alan R. [0000-0002-0747-7317], Ball, Graeme [0000-0002-6526-2306], Boya, Patricia [0000-0003-3045-951X], Ganley, Ian G. [0000-0003-1481-9407], McWilliams, Thomas G., Prescott, Alan R., Villarejo-Zori, Beatriz, Ball, Graeme, Boya, Patricia, Ganley, Ian G., Medical Research Council (UK), Ministerio de Ciencia, Innovación y Universidades (España), Fundación Tatiana Pérez de Guzmán el Bueno, Prescott, Alan R. [0000-0002-0747-7317], Ball, Graeme [0000-0002-6526-2306], Boya, Patricia [0000-0003-3045-951X], Ganley, Ian G. [0000-0003-1481-9407], McWilliams, Thomas G., Prescott, Alan R., Villarejo-Zori, Beatriz, Ball, Graeme, Boya, Patricia, and Ganley, Ian G.
Abstract: Photoreception is pivotal to our experience and perception of the natural world; hence the eye is of prime importance for most vertebrate animals to sense light. Central to visual health is mitochondrial homeostasis, and the selective autophagic turnover of mitochondria (mitophagy) is predicted to play a key role here. Despite studies that link aberrant mitophagy to ocular dysfunction, little is known about the prevalence of basal mitophagy, or its relationship to general autophagy, in the visual system. In this study, we utilize the mito-QC mouse and a closely related general macroautophagy reporter model to profile basal mitophagy and macroautophagy in the adult and developing eye. We report that ocular macroautophagy is widespread, but surprisingly mitophagy does not always follow the same pattern of occurrence. We observe low levels of mitophagy in the lens and ciliary body, in stark contrast to the high levels of general MAP1LC3-dependent macroautophagy in these regions. We uncover a striking reversal of this process in the adult retina, where mitophagy accounts for a larger degree of the macroautophagy taking place, specifically in the photoreceptor neurons of the outer nuclear layer. We also show the developmental regulation of autophagy in a variety of ocular tissues. In particular, mitophagy in the adult mouse retina is reversed in localization during the latter stages of development. Our work thus defines the landscape of mitochondrial homeostasis in the mammalian eye, and in doing so highlights the selective nature of autophagy in vivo and the specificity of the reporters used.
Published: 2019

29. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Author: Weill Cornell Medicine, Associazione Italiana per la Ricerca sul Cancro, Ministero della Salute, Ministero dell'Istruzione, dell'Università e della Ricerca, Ligue Nationale contre le Cancer (France), Agence Nationale de la Recherche (France), Galluzzi, Lorenzo [0000-0003-2257-8500 ], Vitale, Ilio [0000-0002-5918-1841], Boya, Patricia [0000-0003-3045-951X], Kroemer, Guido [0000-0002-9334-4405], Galluzzi, Lorenzo, Vitale, Ilio, Boya, Patricia, Kroemer, Guido, Weill Cornell Medicine, Associazione Italiana per la Ricerca sul Cancro, Ministero della Salute, Ministero dell'Istruzione, dell'Università e della Ricerca, Ligue Nationale contre le Cancer (France), Agence Nationale de la Recherche (France), Galluzzi, Lorenzo [0000-0003-2257-8500 ], Vitale, Ilio [0000-0002-5918-1841], Boya, Patricia [0000-0003-3045-951X], Kroemer, Guido [0000-0002-9334-4405], Galluzzi, Lorenzo, Vitale, Ilio, Boya, Patricia, and Kroemer, Guido
Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
Published: 2018

30. Mitophagy, metabolism, and cell fate

Author: Ministerio de Economía y Competitividad (España), Esteban-Martínez, Lorena [0000-0002-8163-6259], Sierra-Filardi, Elena [0000-0003-4439-2037], Boya, Patricia [0000-0003-3045-951X], Esteban-Martínez, Lorena, Sierra-Filardi, Elena, Boya, Patricia, Ministerio de Economía y Competitividad (España), Esteban-Martínez, Lorena [0000-0002-8163-6259], Sierra-Filardi, Elena [0000-0003-4439-2037], Boya, Patricia [0000-0003-3045-951X], Esteban-Martínez, Lorena, Sierra-Filardi, Elena, and Boya, Patricia
Abstract: Mitophagy is the process by which cells eliminate damaged or superfluous mitochondria by degrading them within lysosomes. We show that during development, selective removal of mitochondria by autophagy induces a metabolic shift toward glycolysis that is essential for differentiation of several cell types. These findings suggest potential applications of cell-fate manipulation strategies targeting mitophagy.
Published: 2017

31. BNIP3L/NIX regulates both mitophagy and pexophagy

Author: Léa P Wilhelm, Juan Zapata‐Muñoz, Beatriz Villarejo‐Zori, Stephanie Pellegrin, Catarina Martins Freire, Ashley M Toye, Patricia Boya, Ian G Ganley, Medical Research Council (UK), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Wilhelm, Léa P., Zapata-Muñoz, Juan, Villarejo-Zori, Beatriz, Toye, Ashley M., Boya, Patricia, Ganley, Ian G., Wilhelm, Léa P. [0000-0001-5926-4666], Zapata-Muñoz, Juan [0000-0003-4747-920X], Villarejo-Zori, Beatriz [0000-0002-5502-4793], Toye, Ashley M. [0000-0003-4395-9396], Boya, Patricia [0000-0003-3045-951X], and Ganley, Ian G. [0000-0003-1481-9407]
Subjects: General Immunology and Microbiology, General Neuroscience, Bristol BioDesign Institute, Mitophagy, Membrane Proteins, General Biochemistry, Genetics and Molecular Biology, Mitochondria, Mitochondrial Proteins, Mice, Macroautophagy, Autophagy, Peroxisomes, Animals, Pexophagy, Apoptosis Regulatory Proteins, Molecular Biology
Abstract: 19 p.-6 fig., Mitochondria and peroxisomes are closely related metabolic organelles, both in terms of origin and in terms of function. Mitochondria and peroxisomes can also be turned over by autophagy, in processes termed mitophagy and pexophagy, respectively. However, despite their close relationship, it is not known if both organelles are turned over under similar conditions, and if so, how this might be coordinated molecularly. Here, we find that multiple selective autophagy pathways are activated upon iron chelation and show that mitophagy and pexophagy occur in a BNIP3L/NIX-dependent manner. We reveal that the outer mitochondrial membrane-anchored NIX protein, previously described as a mitophagy receptor, also independently localises to peroxisomes and drives pexophagy. We show this process happens in vivo, with mouse tissue that lacks NIX having a higher peroxisomal content. We further show that pexophagy is stimulated under the same physiological conditions that activate mitophagy, including cardiomyocyte and erythrocyte differentiation. Taken together, our work uncovers a dual role for NIX, not only in mitophagy but also in pexophagy, thus illustrating the interconnection between selective autophagy pathways., This work was funded by an EMBO Long-Term Fellowship (LPW; ALTF 1077-2018), a grant from the Medical Research Council, UK (IGG; MC_UU_00018/2) and by Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) PGC2018-098557-B-I00 to PB.
Published: 2022
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32. Towards a better understanding of the neuro-developmental role of autophagy in sickness and in health

Author: Pablo Largo-Barrientos, Juan Zapata-Muñoz, Beatriz Villarejo-Zori, Patricia Boya, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Comunidad de Madrid, Zapata-Muñoz, Juan, Boya, Patricia, Largo-Barrientos, Pablo, Zapata-Muñoz, Juan [0000-0003-4747-920X], Boya, Patricia [0000-0003-3045-951X], and Largo-Barrientos, Pablo [0000-0001-9562-645X]
Subjects: Cancer Research, Neuronal autophagy, QH301-705.5, Physiology, Neurogenesis, Neurodevelopment, Metabolic reprogramming, BETA, autism spectrum disorder, Review, Biology, Biochemistry, Genetics and Molecular Biology (miscellaneous), 03 medical and health sciences, PROTEIN-ASSOCIATED NEURODEGENERATION, 0302 clinical medicine, TUBEROUS SCLEROSIS, developmental disorders, CELL, Biology (General), Autism spectrum disorder, AUTISM, IN-VIVO, 030304 developmental biology, 0303 health sciences, Science & Technology, neurodevelopment, Cellular process, Developmental disorders, Autophagy, Cell Biology, DIRECT PHOSPHORYLATION, NEURONAL DEATH, Neural stem cell, 3. Good health, REGULATES AUTOPHAGY, neurogenesis, Toxic proteins, 030220 oncology & carcinogenesis, Medicine, Molecular Medicine, Life Sciences & Biomedicine, neuronal autophagy, FRAGILE-X, Neuroscience, Reprogramming, Homeostasis
Abstract: Autophagy is a critical cellular process by which biomolecules and cellular organelles are degraded in an orderly manner inside lysosomes. This process is particularly important in neurons: these post-mitotic cells cannot divide or be easily replaced and are therefore especially sensitive to the accumulation of toxic proteins and damaged organelles. Dysregulation of neuronal autophagy is well documented in a range of neurodegenerative diseases. However, growing evidence indicates that autophagy also critically contributes to neurodevelopmental cellular processes, including neurogenesis, maintenance of neural stem cell homeostasis, differentiation, metabolic reprogramming, and synaptic remodelling. These findings implicate autophagy in neurodevelopmental disorders. In this review we discuss the current understanding of the role of autophagy in neurodevelopment and neurodevelopmental disorders, as well as currently available tools and techniques that can be used to further investigate this association., Research in the P.B. lab is supported by grant (PGC2018-098557-B-I00) from Spain’s Ministerio Ciencia e Innovación, the Agencia Estatal de Investigación (AEI), the Fondo Europeo de Desarrollo Regional (FEDER), and funding from the European Union’s Horizon 2020 Research and Innova-tion Programme under grant agreement No. 765912, Fundación Tatiana Pérez de Guzmán el Bueno Proyectos en Neurociencia 2018, and Redes de BioMedicina de la Co-munidad de Madrid, BMD-3813. JZM is a recipient of a FPU fellowship (Ministerio de Universidades).
Published: 2021
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33. Regulation of PRKN-independent mitophagy

Author: Ana Lapao, Petra Teresak, Patricia Boya, Zvulun Elazar, Nemanja Subic, Anne Simonsen, Israel Science Foundation, Sagol Institute for Longevity Research, Yeda-Sela Center for Basic Research (Israel), Research Council of Norway, Norwegian Cancer Society, Ministerio de Ciencia, Innovación y Universidades (España), Fundación Tatiana Pérez de Guzmán el Bueno, Comunidad de Madrid, European Commission, Boya, Patricia [0000-0003-3045-951X], Elazar, Zvulun [0000-0002-3231-4464], Simonsen, Anne [0000-0003-4711-7057], Boya, Patricia, Elazar, Zvulun, and Simonsen, Anne
Subjects: 0301 basic medicine, Autophagy receptors, Mitochondrial intermembrane space, Ubiquitin-Protein Ligases, Cellular homeostasis, PINK1, Review, mTORC1, Mitochondrion, Biology, Selective autophagy, 03 medical and health sciences, chemistry.chemical_compound, Mitophagy, Autophagy, Cardiolipin, Inner mitochondrial membrane, Molecular Biology, 030102 biochemistry & molecular biology, Cell Biology, Mitochondria, 3. Good health, Cell biology, 030104 developmental biology, Proto-Oncogene Proteins c-bcl-2, chemistry, Mitochondrial Membranes, Mitochondrial dysfunction, Protein Kinases
Abstract: 37 p.-3 fig.-1 tab., Mitochondria are dynamic, multifunctional cellular organelles that play a fundamental role in maintaining cellular homeostasis. Keeping the quality of mitochondria in check is of essential importance for functioning and survival of the cells. Selective autophagic clearance of flawed mitochondria, a process termed mitophagy, is one of the most prominent mechanisms through which cells maintain a healthy mitochondrial pool. The best-studied pathway through which mitophagy is exerted is the PINK1-PRKN pathway. However, an increasing number of studies have shown an existence of alternative pathways, where different proteins and lipids are able to recruit autophagic machinery independently of PINK1 and PRKN. The significance of PRKN-independent mitophagy pathways is reflected in various physiological and pathophysiological processes, but many questions regarding the regulation and the interplay between these pathways remain open. Here we review the current knowledge and recent progress made in the field of PRKN-independent mitophagy. Particularly we focus on the regulation of various receptors that participate in targeting impaired mitochondria to autophagosomes independently of PRKN., We are grateful for funding from the Israel Science Foundation (Grant #215/19), the Sagol Longevity Foundation, Joint NRF - ISF Research Fund (Grant #3221/19), and the Yeda-Sela Center for Basic Research, as well as the Research Council of Norway through its Centres of Excellence funding scheme (project number 262652 to AS) and FRIPRO (project number 221831 to AS) and the Norwegian Cancer Society (project number 171318 to AS). Research in PB lab is supported by (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) PGC2018-098557-B-I00 Neuroscience Projects from Fundación Tatiana Pérez de Guzmán el Bueno and 2017/BMD-3813 from Comunidad de Madrid. The first authors are supported by a Marie Skłodowska-Curie ETN grant under the European Union’s Horizon 2020 Research and Innovation Programme (Grant Agreement No 765912 DRIVE)
Published: 2021
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34. p38 MAPK priming boosts VSMC proliferation and arteriogenesis by promoting PGC1α-dependent mitochondrial dynamics

Author: Álvaro Sahún-Español, Cristina Clemente, Juan Ignacio Jiménez-Loygorri, Elena Sierra-Filardi, Leticia Herrera-Melle, Aurora Gómez-Durán, Guadalupe Sabio, María Monsalve, Patricia Boya, Alicia G. Arroyo, Ministerio de Ciencia e Innovación (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Unión Europea, Ministerio de Educación, Cultura y Deporte (España), Fundación La Caixa, Comunidad de Madrid (España), Consejo Superior de Investigaciones Científicas (España), Fundación 'la Caixa', Apadrina la Ciencia, CSIC - Residencia de Estudiantes, Comunidad de Madrid, Sahún-Español, Álvaro [0000-0003-3833-5386], Clemente, Cristina [0000-0002-5831-9132], Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Sierra-Filardi, Elena [0000-0003-4439-2037], Herrera-Melle, Leticia [0000-0002-9630-2219], Gómez-Durán, Aurora [0000-0002-5895-6860], Sabio, Guadalupe [0000-0002-2822-0625], Monsalve, María [0000-0003-2796-1453], Boya, Patricia [0000-0003-3045-951X], Arroyo, Alicia G. [0000-0002-1536-3846], Sahún-Español, Álvaro, Clemente, Cristina, Jiménez-Loygorri, Juan Ignacio, Sierra-Filardi, Elena, Herrera-Melle, Leticia, Gómez-Durán, Aurora, Sabio, Guadalupe, Monsalve, María, Boya, Patricia, and Arroyo, Alicia G.
Subjects: Mice, Multidisciplinary, Myocytes, Smooth Muscle, Animals, Matrix Metalloproteinase 17, p38 Mitogen-Activated Protein Kinases, Mitochondrial Dynamics, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Anisomycin, Cells, Cultured, Muscle, Smooth, Vascular, Cell Proliferation
Abstract: 17 p.-6 fig., Vascular smooth muscle cell (VSMC) proliferation is essential for arteriogenesis to restore blood flow after artery occlusion, but the mechanisms underlying this response remain unclear. Based on our previous findings showing increased VSMC proliferation in the neonatal aorta of mice lacking the protease MT4-MMP, we aimed at discovering new players in this process. We demonstrate that MT4-MMP absence boosted VSMC proliferation in vitro in response to PDGF-BB in a cell-autonomous manner through enhanced p38 MAPK activity. Increased phospho-p38 in basal MT4-MMP-null VSMCs augmented the rate of mitochondrial degradation by promoting mitochondrial morphological changes through the co-activator PGC1α as demonstrated in PGC1α−/− VSMCs. We tested the in vivo implications of this pathway in a novel conditional mouse line for selective MT4-MMP deletion in VSMCs and in mice pre-treated with the p38 MAPK activator anisomycin. Priming of p38 MAPK activity in vivo by the absence of the protease MT4-MMP or by anisomycin treatment led to enhanced arteriogenesis and improved flow recovery after femoral artery occlusion. These findings may open new therapeutic opportunities for peripheral vascular diseases., Funding was provided by the Spanish Ministerio de Ciencia e Innovación (AEI/FEDER, UE), SAF2017-83229-R and PID2020-112981RB-I00 (AGA), PID2020-114709RA-I00 (AGD), PID2019-104399RB-I00 (GS), RTI2018-093864-B-I00 (MM), PGC2018-098557-B-I00 (PB), PRE2019-088222 (JIJL) and the Spanish Ministerio de Educación, Cultura y Deporte, FPU15-05802 (LHM). ASE was supported by fellowships from Obra Social La Caixa, Ford-Apadrina La Ciencia and La Residencia de Estudiantes. AGD is an Atracción de Talento M1 Fellow from Comunidad de Madrid (Spain) [2019-T1BMD-14236].
Published: 2022

35. HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

Author: Jerome E. Roger, Angela Armento, Eleni Petridou, Patricia Boya, Marijana Samardzija, Raquel Gómez-Sintes, Eberhart Zrenner, Marius Ueffing, Dragana Trifunović, Christian Grimm, Wadood Haq, Andrea Corna, Mohamed Ali Jarboui, Günther Zeck, François Paquet-Durand, Pedro de la Villa, University of Zurich, Trifunović, Dragana, Pro Retina Foundation, Tistou and Charlotte Kerstan Foundation, German Research Foundation, Swiss National Science Foundation, Ministerio de Ciencia, Innovación y Universidades (España), Samardzija, Marijana, Corna, Andrea, Gómez-Sintes, Raquel, Jarboui, Mohamed Ali, Armento, Angela, Haq, Wadood, Paquet-Durand, Francois, Zrenner, Eberhart, de la Villa, P., Zeck, Günther, Grimm, Christian, Boya, Patricia, Ueffing, Marius, Trifunovic, Dragana, Samardzija, Marijana [0000-0003-0991-4653], Corna, Andrea [0000-0002-3209-6719], Gómez-Sintes, Raquel [0000-0003-2854-6964], Jarboui, Mohamed Ali [0000-0002-5203-235X], Armento, Angela [0000-0002-6357-1500], Haq, Wadood [0000-0003-0890-9780], Paquet-Durand, Francois [0000-0001-7355-5742], Zrenner, Eberhart [0000-0003-2846-9663], de la Villa, P. [0000-0001-9856-6616], Zeck, Günther [0000-0003-3998-9883], Grimm, Christian [0000-0001-9318-4352], Boya, Patricia [0000-0003-3045-951X], Ueffing, Marius [0000-0003-2209-2113], and Trifunovic, Dragana [0000-0003-3168-4196]
Subjects: 10018 Ophthalmology Clinic, MAPK/ERK pathway, Programmed cell death, genetic structures, 610 Medicine & health, Biology, Article, Photoreceptor cell, 1307 Cell Biology, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Retinitis pigmentosa, 1312 Molecular Biology, medicine, Animals, Molecular Biology, 030304 developmental biology, Mice, Inbred C3H, 0303 health sciences, Autophagy, Retinal, Cell Biology, medicine.disease, Cone cell, ddc, 3. Good health, Cell biology, Histone Deacetylase Inhibitors, Mice, Inbred C57BL, Disease Models, Animal, Neuroprotective Agents, medicine.anatomical_structure, Histone, Gene Expression Regulation, chemistry, Intravitreal Injections, Retinal Cone Photoreceptor Cells, biology.protein, sense organs, Neurological disorders, Retinitis Pigmentosa, 030217 neurology & neurosurgery, Neuroscience
Abstract: 16 p.-7 fig., Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of high acuity and color vision and, ultimately to blindness. In RP, a vast number of mutations perturb the structure and function of rod photoreceptors, while cones remain initially unaffected. Extensive rod loss in advanced stages of the disease triggers cone death by a mechanism that is still largely unknown. Here, we show that secondary cone cell death in animal models for RP is associated with increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at late stages of the disease, when the majority of rods have already degenerated, was sufficient to delay cone death and support long-term cone survival in two mouse models for RP, affected by mutations in the phosphodiesterase 6b gene. Moreover, the surviving cones remained light-sensitive, leading to an improvement in visual function. RNA-seq analysis of protected cones demonstrated that HDAC inhibition initiated multi-level protection via regulation of different pro-survival pathways,including MAPK, PI3K-Akt, and autophagy. This study suggests a unique opportunity for targeted pharmacological protection of secondary dying cones by HDAC inhibition and creates hope to maintain vision in RP patients even in advanced disease stages., This work was supported by the ProRetina foundation,the Kerstan Foundation, Deutsche Forschungsgemeinschaft (DFGTR 1238/4-1), Swiss National Science Foundation (31003A_173008),BMBF (FKZ: 01EK1613E), and GC2018-098557-B-I00 from MCIU/AEI/FEDER, UE. RGS is a recipient of a JIN grant RTI2018-098990- J-I00 from MCIU, Spain.
Published: 2020
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36. HIF1α or mitophagy: which drives cardiomyocyte differentiation?

Author: Beatriz Villarejo-Zori, Patricia Boya, Juan Ignacio Jiménez-Loygorri, Ministerio de Ciencia e Innovación (España), European Commission, Boya, Patricia, and Boya, Patricia [0000-0003-3045-951X]
Subjects: Cancer Research, Physiology, lcsh:Medicine, cardiomyocyte, HIFalpha, Biology, Biochemistry, Genetics and Molecular Biology (miscellaneous), nix, 03 medical and health sciences, 0302 clinical medicine, Mitophagy, Cardiomyocyte differentiation, lcsh:QH301-705.5, 030304 developmental biology, Cardiomyocytes, 0303 health sciences, lcsh:R, differentiation, glycolysis, Cell biology, NIX, mitophagy, lcsh:Biology (General), Glycolisis, hif1a, Differentiation, Molecular Medicine, 030217 neurology & neurosurgery
Abstract: 4 p.-1 fig., Research in the P.B. lab is supported by grants PGC2018-098557-B-I00 from Spain’s Ministerio Ciencia e Innovación, and funding from the European Union’s Horizon 2020 re-search and innovation programme under grant agreement No. 765912.
Published: 2020
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37. Ambra1 haploinsufficiency in cd1 mice results in metabolic alterations and exacerbates age-associated retinal degeneration

Author: Ignacio Ramírez-Pardo, Beatriz Villarejo-Zori, Juan Ignacio Jiménez-Loygorri, Elena Sierra-Filardi, Sandra Alonso-Gil, Guillermo Mariño, Pedro de la Villa, Patrick S Fitze, José Manuel Fuentes, Ramón García-Escudero, Deborah A. Ferrington, Raquel Gomez-Sintes, Patricia Boya, European Commission, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Ramírez-Pardo, Ignacio [0000-0003-4873-7274], Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Sierra-Filardi, Elena [0000-0003-4439-2037], Mariño, Guillermo [0000-0003-1960-1677], de la Villa, P. [0000-0001-9856-6616], Fitze, Patrick S. [0000-0002-6298-2471], Fuentes, José M. [0000-0001-6910-2089], García-Escudero, Ramón [0000-0001-5640-6542], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia [0000-0003-3045-951X], Ramírez-Pardo, Ignacio, Jiménez-Loygorri, Juan Ignacio, Sierra-Filardi, Elena, Mariño, Guillermo, de la Villa, P., Fitze, Patrick S., Fuentes, José M., García-Escudero, Ramón, Gómez-Sintes, Raquel, and Boya, Patricia
Subjects: Aging, Retinal pigment, Autophagy, Metabolic alterations, Cell Biology, AMBRA1, Neurodegeneration, Molecular Biology, Retina, Epithelium
Abstract: 22 p.-9 fig., Macroautophagy/autophagy is a key process in the maintenance of cellular homeostasis. The age-dependent decline in retinal autophagy has been associated with photoreceptor degeneration. Retinal dysfunction can also result from damage to the retinal pigment epithelium (RPE), as the RPE-retina constitutes an important metabolic ecosystem that must be finely tuned to preserve visual function. While studies of mice lacking essential autophagy genes have revealed a predisposition to retinal degeneration, the consequences of a moderate reduction in autophagy, similar to that which occurs during physiological aging, remain unclear. Here, we described a retinal phenotype consistent with accelerated aging in mice carrying a haploinsufficiency for Ambra1, a pro-autophagic gene. These mice showed protein aggregation in the retina and RPE, metabolic underperformance, and premature vision loss. Moreover, Ambra1+/gt mice were more prone to retinal degeneration after RPE stress. These findings indicate that autophagy provides crucial support to RPE-retinal metabolism and protects the retina against stress and physiological aging., This work was supported by the H2020 Excellent Science [No. 765912]; Instituto de Salud Carlos III,CiberNed [CB06/05/0041]; Spanish Ministry of Science and Innovation [RTI2018-098990-J-I00]; Spanish Ministry of Science and Innovation [PGC2018-098557-B-I00].
Published: 2022

38. Autophagy in major human diseases

Author: Lorenzo Galluzzi, Hans-Uwe Simon, Augustine M.K. Choi, Qing Zhong, Patrice Codogno, Junying Yuan, Alexandra Stolz, Zvulun Elazar, Eeva-Liisa Eskelinen, Douglas R. Green, José Manuel Bravo-San Pedro, David A. Gewirtz, Anne Simonsen, Sharon A. Tooze, Frank Madeo, María Isabel Colombo, Terje Johansen, Ravi K. Amaravadi, Giulia Petroni, Nicholas T. Ktistakis, Luca Scorrano, Marja Jäättelä, David C. Rubinsztein, Laura Santambrogio, Ivan Dikic, Kay F. Macleod, Kevin M. Ryan, Claudine Kraft, Gian Maria Fimia, Charleen T. Chu, Jennifer Martinez, Carlos López-Otín, Junichi Sadoshima, Gábor Juhász, Vassiliki Karantza, Malene Hansen, Zhenyu Yue, Ken Cadwell, Ana Maria Cuervo, Francesco Cecconi, Mary E. Choi, Eric H. Baehrecke, Patricia Boya, Vojo Deretic, Nektarios Tavernarakis, Alicia Meléndez, Josef M. Penninger, Mauro Piacentini, Tamotsu Yoshimori, Fulvio Reggiori, Sharad Kumar, Andrea Ballabio, Anna Katharina Simon, Federico Pietrocola, Rushika M. Perera, Guido Kroemer, Christian Münz, Noboru Mizushima, Daniel J. Klionsky, Klionsky, Daniel J [0000-0002-7828-8118], Ballabio, Andrea [0000-0003-1381-4604], Boya, Patricia [0000-0003-3045-951X], Cecconi, Francesco [0000-0002-5614-4359], Chu, Charleen T [0000-0002-5052-8271], Codogno, Patrice [0000-0002-5492-3180], Cuervo, Ana Maria [0000-0002-0771-700X], Dikic, Ivan [0000-0001-8156-9511], Fimia, Gian Maria [0000-0003-4438-3325], Gewirtz, David A [0000-0003-0437-4934], Jäättelä, Marja [0000-0001-5950-7111], Johansen, Terje [0000-0003-1451-9578], Kraft, Claudine [0000-0002-3324-4701], Kroemer, Guido [0000-0002-9334-4405], Kumar, Sharad [0000-0001-7126-9814], Lopez-Otin, Carlos [0000-0001-6964-1904], Mizushima, Noboru [0000-0002-6258-6444], Münz, Christian [0000-0001-6419-1940], Perera, Rushika M [0000-0003-2435-2273], Piacentini, Mauro [0000-0003-2919-1296], Reggiori, Fulvio [0000-0003-2652-2686], Scorrano, Luca [0000-0002-8515-8928], Simonsen, Anne [0000-0003-4711-7057], Stolz, Alexandra [0000-0002-3340-439X], Tavernarakis, Nektarios [0000-0002-5253-1466], Tooze, Sharon A [0000-0002-2182-3116], Yoshimori, Tamotsu [0000-0001-9787-3788], Zhong, Qing [0000-0001-6979-955X], Galluzzi, Lorenzo [0000-0003-2257-8500], Pietrocola, Federico [0000-0002-2930-234X], Apollo - University of Cambridge Repository, Klionsky, D. J., Petroni, G., Amaravadi, R. K., Baehrecke, E. H., Ballabio, A., Boya, P., Bravo-San Pedro, J. M., Cadwell, K., Cecconi, F., Choi, A. M. K., Choi, M. E., Chu, C. T., Codogno, P., Colombo, M., Cuervo, A. M., Deretic, V., Dikic, I., Elazar, Z., Eskelinen, E. -L., Fimia, G. M., Gewirtz, D. A., Green, D. R., Hansen, M., Jaattela, M., Johansen, T., Juhasz, G., Karantza, V., Kraft, C., Kroemer, G., Ktistakis, N. T., Kumar, S., Lopez-Otin, C., Macleod, K. F., Madeo, F., Martinez, J., Melendez, A., Mizushima, N., Munz, C., Penninger, J. M., Perera, R., Piacentini, M., Reggiori, F., Rubinsztein, D. C., Ryan, K., Sadoshima, J., Santambrogio, L., Scorrano, L., Simon, H. -U., Simon, A. K., Simonsen, A., Stolz, A., Tavernarakis, N., Tooze, S. A., Yoshimori, T., Yuan, J., Yue, Z., Zhong, Q., Galluzzi, L., Pietrocola, F., Klionsky, Daniel J, Petroni, Giulia, Amaravadi, Ravi K, Baehrecke, Eric H, Kumar, Sharad, Pietrocola, Federico, Lopez‐Otin, Carlos [0000-0001-6964-1904], and University of Zurich
Subjects: Disease, Review, 10263 Institute of Experimental Immunology, Bioinformatics, Imaging, Pathogenesis, metabolic syndromes, 2400 General Immunology and Microbiology, Autophagy/drug effects, Homeostasis, 610 Medicine & health, Chemical Biology & High Throughput, aging, cancer, inflammation, neurodegeneration, Animals, Biomarkers, Gene Expression Regulation, Genetic Predisposition to Disease, Host-Pathogen Interactions, Humans, Organ Specificity, Signal Transduction, Autophagy, Disease Susceptibility, General Neuroscience, Neurodegeneration, 2800 General Neuroscience, Autophagy & Cell Death, medicine.symptom, Model organisms, Reviews, Inflammation, Biology, Biochemistry & Proteomics, General Biochemistry, Genetics and Molecular Biology, metabolic syndrome, Signalling & Oncogenes, 1300 General Biochemistry, Genetics and Molecular Biology, ddc:570, 1312 Molecular Biology, medicine, ddc:610, Molecular Biology, General Immunology and Microbiology, Cancer, Cell Biology, medicine.disease, Preclinical data, EMBO07, 570 Life sciences, biology
Abstract: Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy‐related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders., This review provides an exhaustive overview of the contribution of autophagy to multiple pathological phenotypes in vivo, and discusses the therapeutic potential of autophagy modulation in disease prevention and treatment.
Published: 2021
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39. Lipid dismantling of lens organelles for clear vision

Author: Patricia Boya, Boya, Patricia, and Boya, Patricia [0000-0003-3045-951X]
Subjects: 0303 health sciences, Multidisciplinary, genetic structures, Chemistry, eye diseases, Cell biology, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Lens (anatomy), Organelle, medicine, sense organs, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: 2 p.-1 fig., In the eye, the transparent lens focuses light on the retina. This transparency is achieved during lens development by a newly identified mechanism — whole organelles are destroyed by the degradation of their lipid membranes.
Published: 2021

40. Molecular Alterations in Sporadic and SOD1-ALS Immortalized Lymphocytes: Towards a Personalized Therapy

Author: Daniel Borrego-Hernández, Sebastián Cerdán, Isabel Lastres-Becker, Gracia Porras, Inés Maestro, Alberto García-Redondo, Ángeles Martín-Requero, Marina Arribas-Blázquez, Patricia Boya, Ana Martínez, UAM. Departamento de Bioquímica, Instituto de Investigaciones Biomédicas 'Alberto Sols' (IIBM), Instituto Teófilo Hernando de I+D del Medicamento (ITH), Comunidad de Madrid, European Commission, Instituto de Salud Carlos III, Fundación Española para el Fomento de la Investigación de la Esclerosis Lateral Amiotrófica, Agencia Estatal de Investigación (España), Lastres-Becker, Isabel, Arribas-Blázquez, Marina, Maestro, Inés, Boya, Patricia, Cerdán, Sebastián, García-Redondo, Alberto, Martínez, Ana, Martín-Requero, Ángeles, Lastres-Becker, Isabel [0000-0002-4968-2175], Maestro, Inés [0000-0002-5026-5803], Boya, Patricia [0000-0003-3045-951X], Cerdán, Sebastián [0000-0001-9965-0270], García-Redondo, Alberto [0000-0001-7646-386X], Martínez, Ana [0000-0002-2707-8110], and Martín-Requero, Ángeles [0000-0002-3416-9440]
Subjects: Male, amyotrophic lateral sclerosis, Magnetic Resonance Spectroscopy, medicine.disease_cause, lcsh:Chemistry, Superoxide Dismutase-1, 0302 clinical medicine, oxidative stress, Lymphocytes, Lymphoblast, Precision Medicine, Amyotrophic lateral sclerosis, lcsh:QH301-705.5, Spectroscopy, Cell Line, Transformed, Aged, 80 and over, 0303 health sciences, biology, bioenergetic metabolism, General Medicine, Middle Aged, 3. Good health, Computer Science Applications, Female, medicine.symptom, Signal Transduction, Heterozygote, Cell type, NF-E2-Related Factor 2, Medicina, SOD1, Inflammation, Oxidative phosphorylation, Thiobarbituric Acid Reactive Substances, Article, Catalysis, Proinflammatory cytokine, NRF2, Inorganic Chemistry, Superoxide dismutase, 03 medical and health sciences, Oxygen Consumption, Bioenergetic metabolism, parasitic diseases, medicine, Autophagy, Humans, Metabolomics, RNA, Messenger, Physical and Theoretical Chemistry, Molecular Biology, Aged, 030304 developmental biology, lymphoblast, business.industry, Organic Chemistry, nutritional and metabolic diseases, medicine.disease, lcsh:Biology (General), lcsh:QD1-999, Oxidative stress, inflammation, Mutation, Cancer research, biology.protein, Energy Metabolism, Reactive Oxygen Species, business, Acids, 030217 neurology & neurosurgery
Abstract: 17 p.-6 fig.-1 tab., Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition where motor neurons (MNs) degenerate. Most of the ALS cases are sporadic (sALS), whereas 10% are hereditarily transmitted (fALS), among which mutations are found in the gene that codes for the enzyme superoxide dismutase 1 (SOD1). A central question in ALS field is whether causative mutations display selective alterations not found in sALS patients, or they converge on shared molecular pathways. To identify specific and common mechanisms for designing appropriate therapeutic interventions, we focused on the SOD1-mutated (SOD1-ALS) versus sALS patients. Since ALS pathology involves different cell types other than MNs, we generated lymphoblastoid cell lines (LCLs) from sALS and SOD1-ALS patients and healthy donors and investigated whether they show changes in oxidative stress, mitochondrial dysfunction, metabolic disturbances, the antioxidant NRF2 pathway, inflammatory profile, and autophagic flux. Both oxidative phosphorylation and glycolysis appear to be upregulated in lymphoblasts from sALS and SOD1-ALS. Our results indicate significant differences in NRF2/ARE pathway between sALS and SOD1-ALS lymphoblasts. Furthermore, levels of inflammatory cytokines and autophagic flux discriminate between sALS and SOD1-ALS lymphoblasts. Overall, different molecular mechanisms are involved in sALS and SOD1-ALS patients and thus, personalized medicine should be developed for each case., This research was funded by Comunidad de Madrid (grant ELA_Madrid B2017/BMD-3813 and S2017/BMD-3688), European Commission MSCA-ITN-ETN (grant DRIVE GA: 765912), ISCiii (CIBERNED CB18/05/000 and CB06/05/0089), Fundela (2019/00325/001) for I.L.-B. and AEI (grant PID2019-105600RB-I00) for, A.M. and I.L.-B.
Published: 2021

41. Autophagy induction during stem cell activation plays a key role in salivary gland self-renewal

Author: Idil Orhon, Mirjam Baanstra, Paola Serrano Martinez, Robe Coppes, Fulvio Reggiori, Beatriz Villarejo-Zori, Patricia Boya, Uilke Brouwer, Cecilia Rocchi, European Commission, University of Groningen, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Orhon, Idil [0000-0002-0779-8719], Rocchi, Cecilia [0000-0002-1106-6174], Brouwer, Uilke [0000-0003-3646-5830], Boya, Patricia [0000-0003-3045-951X], Coppes, Robe [0000-0001-5503-1064], Reggiori, Fulvio [0000-0003-2652-2686], Damage and Repair in Cancer Development and Cancer Treatment (DARE), Center for Liver, Digestive and Metabolic Diseases (CLDM), Microbes in Health and Disease (MHD), Orhon, Idil, Rocchi, Cecilia, Brouwer, Uilke, Boya, Patricia, Coppes, Robe, and Reggiori, Fulvio
Subjects: 0301 basic medicine, Maintenance, salivary glands, Stem cells, METABOLISM, MAINTAINS, Biology, Salivary glands, self-renewal, maintenance, 03 medical and health sciences, stem cells, REGENERATION, In vivo, Organoid, medicine, Autophagy, SWITCH, Cell Self Renewal, Progenitor cell, Molecular Biology, 030102 biochemistry & molecular biology, Salivary gland, Regeneration (biology), Cell Differentiation, Cell Biology, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Self-renewal, Stem cell, Flux (metabolism)
Abstract: 17 p.-6 fig, Relatively quiescent tissues like salivary glands (SGs) respond to stimuli such as injury to expand,replace and regenerate. Resident stem/progenitor cells are key in this process because, upon activation, they possess the ability to self-renew. Macroautophagy/autophagy contributes to and regulates differentiation in adult tissues, but an important question is whether this pathway promotes stem cell self-renewal in tissues. We took advantage of a 3D organoid system that allows assessing the self-renewal of mouse SGs stem cells (SGSCs). We found that autophagy in dormant SGSCs has slower flux than self-renewing SGSCs. Importantly, autophagy enhancement upon SGSCs activation is a self-renewal feature in 3D organoid cultures and SGs regenerating in vivo. Accordingly,autophagy ablation in SGSCs inhibits self-renewal whereas pharmacological stimulation promotes self-renewal of mouse and human SGSCs. Thus, autophagy is a key pathway for self-renewal activation in low proliferative adult tissues, and its pharmacological manipulation has the potential to promote tissue regeneration., F.R. is supported by Marie Skłodowska-Curie Cofund [713660], Marie Skłodowska-Curie ITN [765912], ALW Open Program [ALWOP.310]and ZonMW VICI [016.130.606] grants. R.C. and C.R. are supported by the Dutch Cancer Society [Grant number 5792 and 12458]. Patricia Boya is supported by the Ministerio de Ciencia, Innovación y Universidades (MCIU), the Agencia Estatal de Investigación (AEI),the Fondo Europeo de Desarrollo Regional (FEDER) [PGC2018-098557-B-I00] and a Marie Skłodowska-Curie ITN grant [765912]. Idil Orhon is a recipient of a FEBS postdoctoral fellowship and Beatriz Villarejo-Zori of a Fundacion Tatiana Perez de Guzman el Bueno predoctoral fellowhip.
Published: 2021

42. Caty Casas (1967-2020)

Author: Patricia Boya, Boya, Patricia [0000-0003-3045-951X], and Boya, Patricia
Subjects: Cell Biology, Biology, Obituary, Molecular Biology, Classics
Abstract: 3 p.-2 fig.
Published: 2020

43. Serum- and glucocorticoid-induced kinase 1, a new therapeutic target for autophagy modulation in chronic diseases

Author: Ana Martínez, Patricia Boya, Inés Maestro, European Commission, Comunidad de Madrid, Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Maestro, Inés, Boya, Patricia, Martínez, Ana, Maestro, Inés [0000-0002-5026-5803], Boya, Patricia [0000-0003-3045-951X], and Martínez, Ana [0000-0002-2707-8110]
Subjects: 0301 basic medicine, Drug, Therapeutic target, media_common.quotation_subject, Clinical Biochemistry, Aggrephagy, Protein Serine-Threonine Kinases, Immediate-Early Proteins, 03 medical and health sciences, 0302 clinical medicine, Allosteric Regulation, Drug Development, Drug Discovery, Mitophagy, medicine, Autophagy, Animals, Humans, Molecular Targeted Therapy, SGK1, media_common, Pharmacology, urogenital system, Drug discovery, business.industry, Kinase, Neurodegeneration, Neurodegenerative diseases, medicine.disease, 3. Good health, 030104 developmental biology, Kinase inhibitors, 030220 oncology & carcinogenesis, Chronic Disease, Molecular Medicine, business, Neuroscience
Abstract: 13 p.-5 fig.-1 tab., Introduction: Autophagy, a basic cellular degradation pathway essential for survival, is altered both in aging and in many chronic human diseases, including infections, cancer, heart disease, and neurodegeneration. Identifying new therapeutic targets for the control and modulation of autophagy events is therefore of utmost importance in drug discovery. Serum and glucocorticoid activated kinase 1 (SGK1), known for decades for its role in ion channel modulation, is now known to act as a switch for autophagy homeostasis, and has emerged as a novel and important therapeutic target likely to attract considerable research attention in the coming years., Areas covered: In this general review of SGK1 we describe the kinase’s structure and its roles in physiological and pathological contexts. We also discuss small-molecule modulators of SGK1 activity. These modulators are of particular interest to medicinal chemists and pharmacists seeking to develop more potent and selective drug candidates for SGK1, which, despite its key role in autophagy, remains relatively understudied., Expert opinion: The main future challenges in this area are (i) deciphering the role of SGK1 in selective autophagy processes (e.g. mitophagy, lipophagy, and aggrephagy); (ii) identifying selective allosteric modulators of SGK1 with specific biological functions; and (iii) conducting first-in-man clinical studies., Funding support was provided by European Union (EU) (H2020-MSCA-ITN-2017 (grant no. 765912, DRIVE Driving next generation autophagy researchers towards translation); the Autonomous Community of Madrid (CM) (grant no. BMD-3813 ELA_Madrid); and Spanish Ministry of Research and Science (MCIU) and State Research Agency (AEI) (grant numbers PGC2018-098557-B-I00 to P.B. and SAF2016-76693-R to A.M)).
Published: 2020

44. Ambra1 and its role during physiological ageing in the retina

Author: Boya, Patricia, Ramírez-Pardo, Ignacio, Villarejo-Zori, Beatriz, Gómez-Sintes, Raquel, Boya, Patricia [0000-0003-3045-951X], Gómez-Sintes, Raquel [0000-0003-2854-6964], Boya, Patricia, and Gómez-Sintes, Raquel
Abstract: from 2020 ARVO Annual Meeting, canceled because of COVID-19, Purpose : Ambra1 (activating-molecule in Beclin-1-regulated autophagy) is a protein that regulates the early stages of autophagy initiation. Ambra1 haploinsufficiency is linked to autophagy under several pathological conditions such as Alzheimer Disease, autism or multiple system atrophy. In the retina, there is a decline in the autophagy response upon ageing thus we aimed to test if Ambragt/+ haploinsufficiency might affect retinal ageing., Methods : As Ambra1 homozigous animals are embryonic lethal, we have analised the phenotype of Ambra1gt/+ during aging and compared with Ambra1+/+ litermates. We have assessed retinal morphology and function with ERG in animals up to 24 months as well as compared the metabolic profile using mass spectrometry., Results : Our results show that Ambra1gt/+ display premature death in comparison to control littermates. We also observe symptoms of premature retinal ageing in Ambra1gt/+ mice at 15 months old. This tendency was increased in geriatric animals (>20 months) as Ambra1gt/+ displayed increased inflammatory response and a reduction in the photoreceptor layer thickness. Finally, aged Ambra1gt/+ mice displayed a different metabolic signature indicating a misbalance in the purine metabolism and redox status., Conclusions : This data suggest that autophagy deficiency results in a pro-ageing phenotype and impair retinal homeostasis and metabolism.
Published: 2020

45. Age related retinal Ganglion cell susceptibility in context of autophagy deficiency

Author: Elena Sierra-Filardi, Ines Rosignol, Katharina Bell, Natalia Rodriguez-Muela, Francesco Cecconi, Carsten Schmelter, Patricia Boya, Franz H. Grus, Ministerio de Ciencia, Innovación y Universidades (España), European Commission, German Research Foundation, Bell, Katharina [0000-0003-4127-1635], Sierra-Filardi, Elena [0000-0003-4439-2037], Rodríguez-Muela, N. [0000-0003-1065-1870], Schmelter, Carsten [0000-0001-7530-690X], Cecconi, Francesco [0000-0002-5614-4359], Grus, Franz [0000-0003-3978-0967], Boya, Patricia [0000-0003-3045-951X], Bell, Katharina, Sierra-Filardi, Elena, Rodríguez-Muela, N., Schmelter, Carsten, Cecconi, Francesco, Grus, Franz, and Boya, Patricia
Subjects: 0301 basic medicine, Cancer Research, medicine.medical_specialty, genetic structures, Immunology, Cell death in the nervous system, Context (language use), Biology, medicine.disease_cause, Neuroprotection, lcsh:RC254-282, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Internal medicine, Mitophagy, medicine, ddc:610, lcsh:QH573-671, Retina, lcsh:Cytology, Autophagy, Cell Biology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, eye diseases, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Retinal ganglion cell, Optic nerve, sense organs, 030217 neurology & neurosurgery, Oxidative stress
Abstract: 13 p.-6 fig., Glaucoma is a common age-related disease leading to progressive retinal ganglion cell (RGC) death, visual field defects and vision loss and is the second leading cause of blindness in the elderly worldwide. Mitochondrial dysfunction and impaired autophagy have been linked to glaucoma and induction of autophagy shows neuroprotective effects in glaucoma animal models. We have shown that autophagy decreases with aging in the retina and that autophagy can be neuroprotective for RGCs, but it is currently unknown how aging and autophagy deficiency impact RGCs susceptibility and survival. Using the optic nerve crush model in young and olWelcome@1234d Ambra1 +/gt (autophagy/beclin-1 regulator 1+/gt) mice we analysed the contribution of autophagy deficiency on retinal ganglion cell survival in an age dependent context. Interestingly, old Ambra1 +/gt mice showed decreased RGC survival after optic nerve crush in comparison to old Ambra1 +/+, an effect that was not observed in the young animals. Proteomics and mRNA expression data point towards altered oxidative stress response and mitochondrial alterations in old Ambra1 +/gt animals. This effect is intensified after RGC axonal damage, resulting in reduced oxidative stress response showing decreased levels of Nqo1, as well as failure of Nrf2 induction in the old Ambra1 +/gt. Old Ambra1 +/gt also failed to show increase in Bnip3l and Bnip3 expression after optic nerve crush, a response that is found in the Ambra1 +/+ controls. Primary RGCs derived from Ambra1 +/gt mice show decreased neurite projection and increased levels of apoptosis in comparison to Ambra1 +/+ animals. Our results lead to the conclusion that oxidative stress response pathways are altered in old Ambra1 +/gt mice leading to impaired damage responses upon additional external stress factors., This work has been supported by grant PGC2018-098557-B-I00 from Agencia Estatal de Investigación from the Ministerio de Ciencia, Innovación y Universidades and EU. Katharina Bell receives support from DFG (Deutsche Forschungsgemeinschaft) Grant: 6619/1-1.
Published: 2020
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46. New insights into the role of autophagy in retinal and eye diseases

Author: Juan Ignacio Jiménez-Loygorri, Katharina Bell, Patricia Boya, Beatriz Villarejo-Zori, Juan Zapata-Muñoz, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Comunidad de Madrid, Jiménez-Loygorri, Juan Ignacio [0000-0002-3065-9952], Zapata-Muñoz, Juan [0000-0003-4747-920X], Bell, Katharina [0000-0003-4127-1635], Boya, Patricia [0000-0003-3045-951X], Jiménez-Loygorri, Juan Ignacio, Zapata-Muñoz, Juan, Bell, Katharina, and Boya, Patricia
Subjects: Retinal degeneration, Eye Diseases, genetic structures, Clinical Biochemistry, Biology, Biochemistry, Retina, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Lysosome, Autophagy, medicine, Humans, Molecular Biology, 030304 developmental biology, 0303 health sciences, Macular degeneration, Glaucoma, Retinal, General Medicine, Diabetic retinopathy, Retinal dystrophies, medicine.disease, eye diseases, 3. Good health, medicine.anatomical_structure, chemistry, Molecular Medicine, sense organs, Lysosomes, Neuroscience, 030217 neurology & neurosurgery, Retinal Dystrophies
Abstract: 18 p.-4 fig., Autophagy is a fundamental homeostatic pathway that mediates the degradation and recycling of intracellular components. It serves as a key quality control mechanism, especially in non-dividing cells such as neurons. Proteins, lipids, and even whole organelles are engulfed in autophagosomes and delivered to the lysosome for elimination. The retina is a light-sensitive tissue located in the back of the eye that detects and processes visual images. Vision is a highly demanding process, making the eye one of the most metabolically active tissues in the body and photoreceptors display glycolytic metabolism, even in the presence of oxygen. The retina and eye are also exposed to other stressors that can impair their function, including genetic mutations and age-associated changes. Autophagy, among other pathways, is therefore a key process for the preservation of retinal homeostasis. Here, we review the roles of both canonical and non-canonical autophagy in normal retinal function. We discuss the most recent studies investigating the participation of autophagy in eye diseases such as age-related macular degeneration, glaucoma, and diabetic retinopathy and its role protecting photoreceptors in several forms of retinal degeneration. Finally, we consider the therapeutic potential of strategies that target autophagy pathways to treat prevalent retinal and eye diseases., Research in the P.B. lab is supported by funding (PGC2018-098557-B-I00) from Spain's Ministerio Ciencia e Innovación, Agencia Estatal de Investigación (AEI), the Fondo Europeo de Desarrollo Regional (FEDER), the European Union's Horizon 2020 research and innovation program (grant agreement No 765912), the Fundación Tatiana Pérez de Guzmán el Bueno Proyectos en Neurociencia 2018, and Redes de BioMedicina de la Comunidad de Madrid (BMD-3813).
Published: 2021
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47. Autophagy and disease: new insights and challenges ahead

Author: Patricia Boya, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), European Commission, Fundación Tatiana Pérez de Guzmán el Bueno, Comunidad de Madrid, Boya, Patricia, and Boya, Patricia [0000-0003-3045-951X]
Subjects: business.industry, Clinical Biochemistry, Autophagy, Humans, Molecular Medicine, Medicine, General Medicine, Disease, business, Molecular Biology, Biochemistry, Neuroscience
Abstract: 2 p., Research in my laboratory is supported by funding (PGC 2018-098557-B-I00) from Spain's Ministerio Ciencia e Innovación, Agencia Estatal de Investigación (AEI), the Fondo Europeo de Desarrollo Regional (FEDER), the European Union's Horizon 2020 Research and Innovation Program (grant agreement No. 765912), the Fundación Tatiana Pérez de Guzmán el Bueno Proyectos en Neurociencia 2018, and Redes de BioMedicina de la Comunidad de Madrid (BMD-3813).
Published: 2021
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48. A comparative map of macroautophagy and mitophagy in the vertebrate eye

Author: McWilliams, Thomas G., Prescott, Alan R., Villarejo-Zori, Beatriz, Ball, Graeme, Boya, Patricia, Ganley, Ian G., Department of Anatomy, STEMM - Stem Cells and Metabolism Research Program, Medical Research Council (UK), Ministerio de Ciencia, Innovación y Universidades (España), Fundación Tatiana Pérez de Guzmán el Bueno, Prescott, Alan R., Ball, Graeme, Boya, Patricia, Ganley, Ian G., Prescott, Alan R. [0000-0002-0747-7317], Ball, Graeme [0000-0002-6526-2306], Boya, Patricia [0000-0003-3045-951X], and Ganley, Ian G. [0000-0003-1481-9407]
Subjects: retina, MITOCHONDRIAL DYSFUNCTION, genetic structures, lens, mito-QC, ENERGY-METABOLISM, Ciliary body, ORGANIZATION, Eye, Retina, Cornea, Lens, Hyaloid, cornea, Autophagy, OXIDATIVE STRESS, ciliary body, Mitophagy, 1184 Genetics, developmental biology, physiology, 3112 Neurosciences, MOUSE MODEL, Mito-QC, VISUAL CELLS, DEGENERATION, eye, eye diseases, Mitochondria, mitochondria, mitophagy, CELL-DEATH, 1182 Biochemistry, cell and molecular biology, sense organs, 3111 Biomedicine, hyaloid
Abstract: 14 p.-6 fig., Photoreception is pivotal to our experience and perception of the natural world; hence the eye is of prime importance for most vertebrate animals to sense light. Central to visual health is mitochondrial homeostasis, and the selective autophagic turnover of mitochondria (mitophagy) is predicted to play a key role here. Despite studies that link aberrant mitophagy to ocular dysfunction, little is known about the prevalence of basal mitophagy, or its relationship to general autophagy, in the visual system. In this study, we utilize the mito-QC mouse and a closely related general macroautophagy reporter model to profile basal mitophagy and macroautophagy in the adult and developing eye. We report that ocular macroautophagy is widespread, but surprisingly mitophagy does not always follow the same pattern of occurrence. We observe low levels of mitophagy in the lens and ciliary body, in stark contrast to the high levels of general MAP1LC3-dependent macroautophagy in these regions. We uncover a striking reversal of this process in the adult retina, where mitophagy accounts for a larger degree of the macroautophagy taking place, specifically in the photoreceptor neurons of the outer nuclear layer. We also show the developmental regulation of autophagy in a variety of ocular tissues. In particular, mitophagy in the adult mouse retina is reversed in localization during the latter stages of development. Our work thus defines the landscape of mitochondrial homeostasis in the mammalian eye, and in doing so highlights the selective nature of autophagy in vivo and the specificity of the reporters used., This work was funded by grants from the Medical Research Council, UK (IGG; MC_UU_12016/4) and the Ministerio de Ciencia, Innovación y Universidades (PB; PGC2018-098557-B-100). BVZ is supported by a fellowship from the Fundación Tatiana Pérez de Guzmán el Bueno.The Dundee Imaging Facility is supported by the ‘Wellcome Trust Technology Platform’ award (097945/B/11/Z).
Published: 2019

49. Immunological synapse formation induces mitochondrial clustering and mitophagy in dendritic cells

Author: Michael P. Murphy, Olga Criado-García, José Luis Rodríguez-Fernández, Patricia Boya, Laura Gómez-Cabañas, Pilar López-Cotarelo, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Comunidad de Madrid, Gómez-Cabañas, Laura, López-Cotarelo, Pilar, Boya, Patricia, Murphy, Mike [0000-0003-1115-9618], Apollo - University of Cambridge Repository, Gómez-Cabañas, Laura [0000-0003-3759-4116], López-Cotarelo, Pilar [0000-0003-1578-0110], and Boya, Patricia [0000-0003-3045-951X]
Subjects: Male, Fission, Immunological Synapses, T cell, Immunology, Activation, Apoptosis, Expression, mTORC1, Mitochondrion, Lymphocyte Activation, Immunological synapse, 03 medical and health sciences, Mice, 0302 clinical medicine, Flow-cytometry, T-cell, Polarization, Mitophagy, medicine, Autophagy, Immunology and Allergy, Animals, Immunological synapse formation, Chemistry, Depolarization, ROS, Dendritic Cells, Cell biology, Mitochondria, Mice, Inbred C57BL, medicine.anatomical_structure, Antioxidant, 030215 immunology
Abstract: 9 p.-8 fig., The immunological synapse (IS) is a superstructure formed during T cell activation at the zone of contact between T cells and dendritic cells (DCs). The IS includes specific molecular components in the T cell and DCs sides that may result in different functionality. Most of the studies on the IS have focused on the T cell side of this structure and, in contrast, the information available on the IS of DCs is sparse. Autophagy is a cellular process involved in the clearance of damaged proteins and organelles via lysosomal degradation. Mitophagy is the selective autophagy of damaged mitochondria. In this study, it is shown that IS formation induces clustering of mitochondria in the IS of DCs and partial depolarization of these organelles. At the IS of the DCs also accumulate autophagy and mitophagy markers, even when the kinase complex mTORC1, an inhibitor of the autophagy, is active. Together the results presented indicate that IS formation induces local clustering of mitochondria and mitophagy, which could be a homeostatic mechanism to control the quality of mitochondria in this region. The data underline the complexity of the regulatory mechanisms operating in the IS of DCs., This work was supported by Grants SAF-2014-53151-R (Ministerio de Economía y Competitividad), SAF2017-83306-R (Ministerio de Ciencia, Innovación y Universidades), RD08/0075 (Red de Inflamación y Enfermedades Reumáticas [Redes Temáticas de Investigación Cooperativa en Salud Program/Instituto de Salud Carlos III]), and S2010/BMD-2350 (Consejería de Educación y Empleo from Comunidad de Madrid [Raphyme]) (to J.L.R.-F.). L.G.-C. and P.L.-C were supported by fellowships Formación del Profesorado Universitario and Formación de Personal Investigador, conferred by the Ministerio de Educación y Ciencia and Ministerio de Economía y Competitividad, respectively. M.P.M. was supported by the Medical Research Council UK (MC_U105663142) and a Wellcome Trust Investigator Award (110159/Z/15/Z).
Published: 2019

50. Driving next-generation autophagy researchers towards translation (DRIVE), an international PhD training program on autophagy

Author: Fulvio Reggiori, Judith Farres, Ana Martínez, Eeva-Liisa Eskelinen, Vladimir Kirkin, Charlotte Primard, Claudine Kraft, Heinz Jungbluth, Patricia Boya, Zvulun Elazar, Ole Pless, Anne Simonsen, Patrice Codogno, Tassula Proikas-Cezanne, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Kraft, Claudine [0000-0002-3324-4701], Boya, Patricia [0000-0003-3045-951X], Codogno, Patrice [0000-0002-5492-3180], Elazar, Zvulun [0000-0002-3231-4464], Eskelinen, Eeva-Liisa [0000-0003-0006-7785], Kirkin, Vladimir [0000-0002-8049-3663], Jungbluth, Heinz [0000-0002-7159-3427], Martínez, Ana [0000-0002-2707-8110], Pless, Ole [0000-0002-1468-316X], Proikas-Cezanne, Tassula [0000-0001-6934-132X], Simonsen, Anne [0000-0003-4711-7057], Reggiori, Fulvio [0000-0003-2652-2686], Kraft, Claudine, Boya, Patricia, Codogno, Patrice, Elazar, Zvulun, Eskelinen, Eeva-Liisa, Kirkin, Vladimir, Jungbluth, Heinz, Martínez, Ana, Pless, Ole, Proikas-Cezanne, Tassula, Simonsen, Anne, Reggiori, Fulvio, Microbes in Health and Disease (MHD), Center for Liver, Digestive and Metabolic Diseases (CLDM), Publica, Molecular and Integrative Biosciences Research Programme, Biochemistry and Biotechnology, and University of Helsinki
Subjects: 0301 basic medicine, Biomedical Research, European community, consortium, Dissemination, Network, Biology, ta3111, clinical, dissemination, 03 medical and health sciences, Clinical, Autophagy, Raining, Humans, Education, Graduate, European Community, Molecular Biology, 030102 biochemistry & molecular biology, translational, Translational, ta1182, Translation (biology), Cell Biology, Research Personnel, 3. Good health, Europe, 030104 developmental biology, network, Commentary, 1182 Biochemistry, cell and molecular biology, Engineering ethics, Training program, raining, Consortium
Abstract: DRIVE is supported by a MarieSkłodowska-Curie ETN grant under theEuropean Union’s Horizon 2020 Research and Innovation Programme(Grant Agreement No 765912). P.B. is also supported by the Ministerio de Ciencia, Innovación y Universidades (BFU2015-65623) and by Redes de laComunidad de Madrid 2017/BMD-3813. Work in P.C. laboratory is sup-ported by institutional fundings from INSERM, CNRS and University ParisDescartes and by grants from Agence Nationale pour la Recherche (ANR) andFondation pour la Recherche Médicale(FRM). Z.E. research is supported bythe Israel Science Foundation ISF, the Legacy Heritage Fund and theWeizmann Institute Minerva center. E.-L.E. is also supported by TheAcademy of Finland project grant (286787), by Magnus EhrnroothFoundation, and by COST Action 15138 Transautophagy. V.K. is also sup-ported by the CRUK programme grant C2739/A22897. C.K. is also supportedby funding from the Vienna Science and Technology Fund (WWTF, VRG10-001) from the FWF Austrian Science Fund (P28113-B28), from the EuropeanResearch Council (ERC) under the European Union’s Horizon 2020 Researchand Innovation Programme (grant agreement No 769065), and from theEMBO Young Investigator Program. H.J. is supported by a grant fromAction Medical Research (Grant reference GN 2446), United Kingdom. O.P.is also supported by the German Federal Ministry of Education and Research(BMBF) (01EK1608B and 13GW0128B). T.P.-C. is also supported by theGerman Research Foundation (Deutsche Forschungsgemeinschaft, DFG);SFB/TRR 209 (project B02); FOR 2625 (project 1). A.S. is also supported bythe Research Council of Norway (project # 221831 and through its Centres ofExcellence funding scheme project # 262652) and the Norwegian CancerSociety (project #190251). F.R. is also supported by ZonMW VICI(016.130.606), ZonMW TOP (91217002), ALW Open Programme(ALWOP.310) and Marie Skłodowska-Curie Cofund (713660) grant, DRIVEis supported by a MarieSkłodowska-Curie ETN grant under the European Union’s Horizon 2020 Research and Innovation Programme(Grant Agreement No 765912). P.B. is also supported by the Ministerio deCiencia, Innovación y Universidades (BFU2015-65623) and by Redes de la Comunidad de Madrid 2017/BMD-3813. Work in P.C. laboratory is sup-ported by institutional fundings from INSERM, CNRS and University ParisDescartes and by grants from Agence Nationale pour la Recherche (ANR) andFondation pour la Recherche Médicale(FRM). Z.E. research is supported bythe Israel Science Foundation ISF, the Legacy Heritage Fund and theWeizmann Institute Minerva center. E.-L.E. is also supported by The Academy of Finland project grant (286787), by Magnus EhrnroothFoundation, and by COST Action 15138 Transautophagy. V.K. is also sup-ported by the CRUK programme grant C2739/A22897. C.K. is also supportedby funding from the Vienna Science and Technology Fund (WWTF, VRG10-001) from the FWF Austrian Science Fund (P28113-B28), from the EuropeanResearch Council (ERC) under the European Union’s Horizon 2020 Researchand Innovation Programme (grant agreement No 769065), and from the EMBO Young Investigator Program. H.J. is supported by a grant fromAction Medical Research (Grant reference GN 2446), United Kingdom. O.P.is also supported by the German Federal Ministry of Education and Research(BMBF) (01EK1608B and 13GW0128B). T.P.-C. is also supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG);SFB/TRR 209 (project B02); FOR 2625 (project 1). A.S. is also supported by the Research Council of Norway (project # 221831 and through its Centres ofExcellence funding scheme project # 262652) and the Norwegian CancerSociety (project #190251). F.R. is also supported by ZonMW VICI(016.130.606), ZonMW TOP (91217002), ALW Open Programme(ALWOP.310) and Marie Skłodowska-Curie Cofund (713660) grants.
Published: 2019
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