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

Author

Vitale, Ilio, Pietrocola, Federico, Guilbaud, Emma, Aaronson, Stuart A, Abrams, John M, Adam, Dieter, 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 JM, Bianchi, Marco E, Blagosklonny, Mikhail V, Blander, J Magarian, Blandino, Giovanni, Blomgren, Klas, Borner, Christoph, Bortner, Carl D, Bove, Pierluigi, Boya, Patricia, Brenner, Catherine, Broz, Petr, Brunner, Thomas, 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, Bart, 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 Maria, Galassi, Claudia, Ganini, Carlo, Garcia-Saez, 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, and Kanneganti, Thirumala-Devi

Subjects
Biochemistry and Cell Biology, Biological Sciences, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Generic health relevance, Good Health and Well Being, Animals, Humans, Apoptosis, Cell Death, Caspases, Carcinogenesis, Mammals, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
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

9. Bacteria‐instructed B cells cross‐prime naïve CD8+ T cells triggering effective cytotoxic responses

Author

García‐Ferreras, Raquel, Osuna‐Pérez, Jesús, Ramírez‐Santiago, Guillermo, Méndez‐Pérez, Almudena, Acosta‐Moreno, Andrés M, Del Campo, Lara, Gómez‐Sánchez, María J, Iborra, Marta, Herrero‐Fernández, Beatriz, González‐Granado, José M, Sánchez‐Madrid, Francisco, Carrasco, Yolanda R, Boya, Patricia, Martínez‐Martín, Nuria, and Veiga, Esteban

Published
2023
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10. Beth Levine in memoriam

Author

An, Zhenyi, Ballabio, Andrea, Bennett, Lynda, Boya, Patricia, Cecconi, Francesco, Chiang, Wei-Chung, Codogno, Patrice, Colombo, Maria Isabel, Cuervo, Ana Maria, Debnath, Jayanta, Deretic, Vojo, Dikic, Ivan, Dionne, Keith, Dong, Xiaonan, Elazar, Zvulun, Galluzzi, Lorenzo, Gentile, Frank, Griffin, Diane E, Hansen, Malene, Hardwick, J Marie, He, Congcong, Huang, Shu-Yi, Hurley, James, Jackson, William T, Jozefiak, Cindy, Kitsis, Richard N, Klionsky, Daniel J, Kroemer, Guido, Meijer, Alfred J, Melendez, Alicia, Melino, Gerry, Mizushima, Noboru, Murphy, Leon O, Nixon, Ralph, Orvedahl, Anthony, Pattingre, Sophie, Piacentini, Mauro, Reggiori, Fulvio, Ross, Theodora, Rubinsztein, David C, Ryan, Kevin, Sadoshima, Junichi, Schreiber, Stuart L, Scott, Frederick, Sebti, Salwa, Shiloh, Michael, Shoji, Sanae, Simonsen, Anne, Smith, Haley, Sumpter, Kathryn M, Thompson, Craig B, Thorburn, Andrew, Thumm, Michael, Tooze, Sharon, Vaccaro, Maria I, Virgin, Herbert W, Wang, Fei, White, Eileen, Xavier, Ramnik J, Yoshimori, Tamotsu, Yuan, Junying, Yue, Zhenyu, and Zhong, Qing

Subjects
Biochemistry and Cell Biology, Biological Sciences, Biochemistry & Molecular Biology, Biochemistry and cell biology
Published
2020

11. 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

12. 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

13. 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

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

Author

Gomez-Sintes, Raquel, Xin, Qisheng, Jimenez-Loygorri, Juan Ignacio, McCabe, Mericka, Diaz, Antonio, Garner, Thomas P., Cotto-Rios, Xiomaris M., Wu, Yang, Dong, Shuxian, Reynolds, Cara A., Patel, Bindi, de la Villa, Pedro, Macian, Fernando, Boya, Patricia, Gavathiotis, Evripidis, and Cuervo, Ana Maria

Published
2022
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17. Fast and quantitative mitophagy assessment by flow cytometry using the mito-QC reporter.

Author

Ignacio Jiménez-Loygorri, Juan, Jiménez-García, Carlos, Viedma-Poyatos, Álvaro, and Boya, Patricia

Subjects
CYTOCHROME c, BIOENERGETICS, FLOW cytometry, MITOCHONDRIAL DNA, MITOCHONDRIA
Abstract

Mitochondrial quality control is finely tuned bymitophagy, the selective degradation of mitochondria through autophagy, and mitochondrial biogenesis. Removal of damaged mitochondria is essential to preserve cellular bioenergetics and prevent detrimental events such as sustained mitoROS production, pro-apoptotic cytochrome c release or mtDNA leakage. The array of tools available to study mitophagy is very limited but in constant development. Almost a decade ago, we developed a method to assess mitophagy flux using MitoTracker Deep Red in combination with lysosomal inhibitors. Now, using the novel tandem-fluorescence reporter mito-QC (mCherry-GFP-FIS1101-152) that allows to differentiate between healthy mitochondria (mCherry+GFP+) and mitolysosomes (mCherry+GFP-), we have developed a robust and quantitative method to assess mitophagy by flow cytometry. This approach has been validated in ARPE-19 cells using PINK1/Parkindependent (CCCP) and PINK1/Parkin-independent (DFP) positive controls and complementary techniques. Furthermore, we show that the mito-QC reporter can be multiplexed, especially if using spectral flow cytometry, to simultaneously study other cellular parameters such as viability or ROS production. Using this technique, we evaluated and characterized two prospective mitophagy inducers and further dissected their mechanism of action. Finally, using mito-QC reporter mice, we developed a protocol to measure mitophagy levels in the retina ex vivo. This novel methodology will propelmitophagy research forward and accelerate the discovery of novel mitophagy modulators. [ABSTRACT FROM AUTHOR]

Published
2024
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18. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Author

Galluzzi, Lorenzo, Vitale, Ilio, Aaronson, Stuart A, Abrams, John M, Adam, Dieter, Agostinis, Patrizia, Alnemri, Emad S, Altucci, Lucia, Amelio, Ivano, Andrews, David W, Annicchiarico-Petruzzelli, Margherita, Antonov, Alexey V, Arama, Eli, Baehrecke, Eric H, Barlev, Nickolai A, Bazan, Nicolas G, Bernassola, Francesca, Bertrand, Mathieu JM, Bianchi, Katiuscia, Blagosklonny, Mikhail V, Blomgren, Klas, Borner, Christoph, Boya, Patricia, Brenner, Catherine, Campanella, Michelangelo, Candi, Eleonora, Carmona-Gutierrez, Didac, Cecconi, Francesco, Chan, Francis K-M, Chandel, Navdeep S, Cheng, Emily H, Chipuk, Jerry E, Cidlowski, John A, Ciechanover, Aaron, Cohen, Gerald M, Conrad, Marcus, Cubillos-Ruiz, Juan R, Czabotar, Peter E, D’Angiolella, Vincenzo, Dawson, Ted M, Dawson, Valina L, De Laurenzi, Vincenzo, De Maria, Ruggero, Debatin, Klaus-Michael, DeBerardinis, Ralph J, Deshmukh, Mohanish, Di Daniele, Nicola, Di Virgilio, Francesco, Dixit, Vishva M, Dixon, Scott J, Duckett, Colin S, Dynlacht, Brian D, El-Deiry, Wafik S, Elrod, John W, Fimia, Gian Maria, Fulda, Simone, García-Sáez, Ana J, Garg, Abhishek D, Garrido, Carmen, Gavathiotis, Evripidis, Golstein, Pierre, Gottlieb, Eyal, Green, Douglas R, Greene, Lloyd A, Gronemeyer, Hinrich, Gross, Atan, Hajnoczky, Gyorgy, Hardwick, J Marie, Harris, Isaac S, Hengartner, Michael O, Hetz, Claudio, Ichijo, Hidenori, Jäättelä, Marja, Joseph, Bertrand, Jost, Philipp J, Juin, Philippe P, Kaiser, William J, Karin, Michael, Kaufmann, Thomas, Kepp, Oliver, Kimchi, Adi, Kitsis, Richard N, Klionsky, Daniel J, Knight, Richard A, Kumar, Sharad, Lee, Sam W, Lemasters, John J, Levine, Beth, Linkermann, Andreas, Lipton, Stuart A, Lockshin, Richard A, López-Otín, Carlos, Lowe, Scott W, Luedde, Tom, Lugli, Enrico, MacFarlane, Marion, Madeo, Frank, Malewicz, Michal, Malorni, Walter, and Manic, Gwenola

Subjects
Biochemistry and Cell Biology, Biological Sciences, Animals, Cell Death, Humans, Lysosomes, Mitochondrial Membrane Transport Proteins, Mitochondrial Permeability Transition Pore, Necrosis, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
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

20. Molecular definitions of autophagy and related processes

Author

Galluzzi, Lorenzo, Baehrecke, Eric H, Ballabio, Andrea, Boya, Patricia, Pedro, José Manuel Bravo‐San, Cecconi, Francesco, Choi, Augustine M, Chu, Charleen T, Codogno, Patrice, Colombo, Maria Isabel, Cuervo, Ana Maria, Debnath, Jayanta, Deretic, Vojo, Dikic, Ivan, Eskelinen, Eeva‐Liisa, Fimia, Gian Maria, Fulda, Simone, Gewirtz, David A, Green, Douglas R, Hansen, Malene, Harper, J Wade, Jäättelä, Marja, Johansen, Terje, Juhasz, Gabor, Kimmelman, Alec C, Kraft, Claudine, Ktistakis, Nicholas T, Kumar, Sharad, Levine, Beth, Lopez‐Otin, Carlos, Madeo, Frank, Martens, Sascha, Martinez, Jennifer, Melendez, Alicia, Mizushima, Noboru, Münz, Christian, Murphy, Leon O, Penninger, Josef M, Piacentini, Mauro, Reggiori, Fulvio, Rubinsztein, David C, Ryan, Kevin M, Santambrogio, Laura, Scorrano, Luca, Simon, Anna Katharina, Simon, Hans‐Uwe, Simonsen, Anne, Tavernarakis, Nektarios, Tooze, Sharon A, Yoshimori, Tamotsu, Yuan, Junying, Yue, Zhenyu, Zhong, Qing, and Kroemer, Guido

Subjects
Animals, Autophagy, Caenorhabditis elegans, Drosophila melanogaster, Gene Regulatory Networks, Mice, Saccharomyces cerevisiae, Terminology as Topic, chaperone-mediated autophagy, LC3-associated phagocytosis, microautophagy, mitophagy, xenophagy, LC3‐associated phagocytosis, chaperone‐mediated autophagy, Biological Sciences, Information and Computing Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Over the past two decades, the molecular machinery that underlies autophagic responses has been characterized with ever increasing precision in multiple model organisms. Moreover, it has become clear that autophagy and autophagy-related processes have profound implications for human pathophysiology. However, considerable confusion persists about the use of appropriate terms to indicate specific types of autophagy and some components of the autophagy machinery, which may have detrimental effects on the expansion of the field. Driven by the overt recognition of such a potential obstacle, a panel of leading experts in the field attempts here to define several autophagy-related terms based on specific biochemical features. The ultimate objective of this collaborative exchange is to formulate recommendations that facilitate the dissemination of knowledge within and outside the field of autophagy research.

Published
2017

21. Mitophagy in mitosis: more than a myth

Author

Esteban-Martinez, Lorena, Domenech, Elena, Boya, Patricia, Salazar Roa, María, Malumbres, Marcos, Esteban-Martinez, Lorena, Domenech, Elena, Boya, Patricia, Salazar Roa, María, and Malumbres, Marcos

Abstract

Work in the authors’ laboratories is funded by grants from MINECO (SAF2012-36079 to PB and SAF201238215, SAF2014-57791-REDC, and BFU2014-52125-REDT to MM), and Comunidad de Madrid (S2010/BMD2470)., An attractive strategy for cancer therapy is to stop cell proliferation by means of agents that directly arrest the cell cycle. Microtubule poisons such as taxanes block mitosis, eventually leading to cell death in a process frequently known as mitotic catastrophe. However, some cells are able to bypass this mitotic arrest and survive, thus contributing to chemoresistance to those therapies. We have recently observed that mitotic arrest induces an early autophagic flux response that results in autophagy-dependent mitochondrial degradation and a dramatic energetic deficit. The subsequent increase in the AMP/ATP ratio results in the activation of the metabolic sensor AMPK followed by phosphorylation and activation of PFKFB3, an enzyme required for glycolysis. Thus, mitophagy can be considered as a critical effector of the therapeutic effect of mitotic therapies, while both AMPK and PFKFB3 are critical for survival. The manipulation of these molecular routes may therefore have therapeutic benefits in the presence of microtubule poisons., Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Biológicas, TRUE, pub

Published
2024

22. AMPK and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest

Author

Domenech, Elena, Maestre, Carolina, Esteban-Martínez, Lorena, Partida, David, Pascual, Rosa, Fernández-Miranda, Gonzalo, Seco, Esther, Campos-Olivas, Ramón, Pérez, Manuel, Megias, Diego, Allen, Katherine, Lopez, Miguel, K. Saha, Asish, Velasco, Guillermo, Rial, Eduardo, Mendez, Raúl, Boya, Patricia, Salazar Roa, María, Malumbres, Marcos, Domenech, Elena, Maestre, Carolina, Esteban-Martínez, Lorena, Partida, David, Pascual, Rosa, Fernández-Miranda, Gonzalo, Seco, Esther, Campos-Olivas, Ramón, Pérez, Manuel, Megias, Diego, Allen, Katherine, Lopez, Miguel, K. Saha, Asish, Velasco, Guillermo, Rial, Eduardo, Mendez, Raúl, Boya, Patricia, Salazar Roa, María, and Malumbres, Marcos

Abstract

E.D., C.M. and M.S.-R. were supported by the Spanish Fondo de Investigaciones Sanitarias (Madrid), MINECO (Juan de la Cierva programme) and Asociación Española contra el Cáncer (AECC), respectively. L.E.-M. is a recipient of a JAE predoctoral fellowship from the CSIC. A.K.S. was supported by USPHS grants RO1DK19514, RO1DK67509. G.V. was supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO) and Fondo Europeo de Desarrollo Regional (FEDER) (PI12/02248), Fundació La Marató de TV3 (m12 20134031), and Fundación Mutua Madrileña (AP101042012). M.L. was supported by the European Community’s Seventh Framework Programme under grant agreement no. 281854—the ObERStress (European Research Council project). E.R. was financially supported by a MINECO grant (SAF 2010-20256). Work in the R.M. laboratory was supported by the Fundación Botín, Banco Santander and MINECO (BFU2011-30121, BFU2014-52125-REDT and Consolider RNAREG CSD2009-00080). Work in the P.B. laboratory is supported by a grant from the Spanish Ministry for Economy and Competitiveness (MINECO; SAF2012-36079). Work in the M.M. laboratory was supported by grants from the MINECO (SAF2012-38215), Consolider-Ingenio 2010 Programme (SAF2014-57791-REDC), Excellence Network CellSYS (BFU2014-52125-REDT), the OncoCycle Programme (S2010/BMD-2470) from the Comunidad de Madrid, Worldwide Cancer Research (WCR no. 15-0278), and the European Union Seventh Framework Programme (MitoSys project; HEALTH-F5-2010-241548)., Blocking mitotic progression has been proposed as an attractive therapeutic strategy to impair proliferation of tumour cells. However, how cells survive during prolonged mitotic arrest is not well understood. We show here that survival during mitotic arrest is affected by the special energetic requirements of mitotic cells. Prolonged mitotic arrest results in mitophagy-dependent loss of mitochondria, accompanied by reduced ATP levels and the activation of AMPK. Oxidative respiration is replaced by glycolysis owing to AMPK-dependent phosphorylation of PFKFB3 and increased production of this protein as a consequence of mitotic-specific translational activation of its mRNA. Induction of autophagy or inhibition of AMPK or PFKFB3 results in enhanced cell death in mitosis and improves the anti-tumoral efficiency of microtubule poisons in breast cancer cells. Thus, survival of mitotic-arrested cells is limited by their metabolic requirements, a feature with potential implications in cancer therapies aimed to impair mitosis or metabolism in tumour cells., Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Biológicas, TRUE, pub

Published
2024

24. 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

25. 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

26. 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

27. 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. 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, Galluzzi, Lorenzo, 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. 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

28. Autophagy in major human diseases

Author

Klionsky, Daniel J, Petroni, Giulia, Amaravadi, Ravi K, Baehrecke, Eric H, Ballabio, Andrea, Boya, Patricia, Bravo‐San Pedro, José Manuel, Cadwell, Ken, Cecconi, Francesco, Choi, Augustine M K, Choi, Mary E, Chu, Charleen T, Codogno, Patrice, Colombo, Maria Isabel, Cuervo, Ana Maria, Deretic, Vojo, Dikic, Ivan, Elazar, Zvulun, Eskelinen, Eeva‐Liisa, Fimia, Gian Maria, Gewirtz, David A, Green, Douglas R, Hansen, Malene, Jäättelä, Marja, Johansen, Terje, Juhász, Gábor, Karantza, Vassiliki, Kraft, Claudine, Kroemer, Guido, Ktistakis, Nicholas T, Kumar, Sharad, Lopez‐Otin, Carlos, Macleod, Kay F, Madeo, Frank, Martinez, Jennifer, Meléndez, Alicia, Mizushima, Noboru, Münz, Christian, Penninger, Josef M, Perera, Rushika M, Piacentini, Mauro, Reggiori, Fulvio, Rubinsztein, David C, Ryan, Kevin M, Sadoshima, Junichi, Santambrogio, Laura, Scorrano, Luca, Simon, Hans‐Uwe, Simon, Anna Katharina, Simonsen, Anne, Stolz, Alexandra, Tavernarakis, Nektarios, Tooze, Sharon A, Yoshimori, Tamotsu, Yuan, Junying, Yue, Zhenyu, Zhong, Qing, Galluzzi, Lorenzo, and Pietrocola, Federico

Published
2021
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29. Acyl-CoA-Binding Protein Is a Lipogenic Factor that Triggers Food Intake and Obesity

Author

Bravo-San Pedro, José M., Sica, Valentina, Martins, Isabelle, Pol, Jonathan, 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, Clément, Karine, Pelloux, Veronique, Rohia, Alili, Pattou, François, Raverdy, Violeta, Caiazzo, Robert, Denis, Raphaël G.P., Boya, Patricia, Galluzzi, Lorenzo, Madeo, Frank, Migrenne-Li, Stéphanie, Cruciani-Guglielmacci, Céline, Tavernarakis, Nektarios, López-Otín, Carlos, Magnan, Christophe, and Kroemer, Guido

Published
2019
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32. Guidelines for the use and interpretation of assays for monitoring autophagy.

Author

Klionsky, Daniel J, Abdalla, Fabio C, Abeliovich, Hagai, Abraham, Robert T, Acevedo-Arozena, Abraham, Adeli, Khosrow, Agholme, Lotta, Agnello, Maria, Agostinis, Patrizia, Aguirre-Ghiso, Julio A, Ahn, Hyung Jun, Ait-Mohamed, Ouardia, Ait-Si-Ali, Slimane, Akematsu, Takahiko, Akira, Shizuo, Al-Younes, Hesham M, Al-Zeer, Munir A, Albert, Matthew L, Albin, Roger L, Alegre-Abarrategui, Javier, Aleo, Maria Francesca, Alirezaei, Mehrdad, Almasan, Alexandru, Almonte-Becerril, Maylin, Amano, Atsuo, Amaravadi, Ravi, Amarnath, Shoba, Amer, Amal O, Andrieu-Abadie, Nathalie, Anantharam, Vellareddy, Ann, David K, Anoopkumar-Dukie, Shailendra, Aoki, Hiroshi, Apostolova, Nadezda, Arancia, Giuseppe, Aris, John P, Asanuma, Katsuhiko, Asare, Nana YO, Ashida, Hisashi, Askanas, Valerie, Askew, David S, Auberger, Patrick, Baba, Misuzu, Backues, Steven K, Baehrecke, Eric H, Bahr, Ben A, Bai, Xue-Yuan, Bailly, Yannick, Baiocchi, Robert, Baldini, Giulia, Balduini, Walter, Ballabio, Andrea, Bamber, Bruce A, Bampton, Edward TW, Bánhegyi, Gábor, Bartholomew, Clinton R, Bassham, Diane C, Bast, Robert C, Batoko, Henri, Bay, Boon-Huat, Beau, Isabelle, Béchet, Daniel M, Begley, Thomas J, Behl, Christian, Behrends, Christian, Bekri, Soumeya, Bellaire, Bryan, Bendall, Linda J, Benetti, Luca, Berliocchi, Laura, Bernardi, Henri, Bernassola, Francesca, Besteiro, Sébastien, Bhatia-Kissova, Ingrid, Bi, Xiaoning, Biard-Piechaczyk, Martine, Blum, Janice S, Boise, Lawrence H, Bonaldo, Paolo, Boone, David L, Bornhauser, Beat C, Bortoluci, Karina R, Bossis, Ioannis, Bost, Frédéric, Bourquin, Jean-Pierre, Boya, Patricia, Boyer-Guittaut, Michaël, Bozhkov, Peter V, Brady, Nathan R, Brancolini, Claudio, Brech, Andreas, Brenman, Jay E, Brennand, Ana, Bresnick, Emery H, Brest, Patrick, Bridges, Dave, Bristol, Molly L, Brookes, Paul S, Brown, Eric J, and Brumell, John H

Subjects
Animals, Humans, Biological Assay, Models, Biological, Autophagy, Generic health relevance, autolysosome, autophagosome, flux, LC3, lysosome, phagophore, stress, vacuole, Biochemistry and Cell Biology, Biochemistry & Molecular Biology
Abstract

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

Published
2012

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

Author

Maestro, Ines, Madruga, Enrique, Boya, Patricia, and Martínez, Ana

Subjects
NEUROPROTECTIVE agents, CHEMICAL inhibitors, PROTEIN kinase inhibitors
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. [ABSTRACT FROM AUTHOR]

Published
2023
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36. 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

37. 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

38. 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

39. 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

40. 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

41. Autophagy in the eye: from physiology to pathophysology

Author

Liton, Paloma B., primary, Boesze-Battaglia, Kathleen, additional, Boulton, Michael E., additional, Boya, Patricia, additional, Ferguson, Thomas A., additional, Ganley, Ian G., additional, Kauppinnen, Anu, additional, Laurie, Gordon W., additional, Mizushima, Noboru, additional, Morishita, Hideaki, additional, Russo, Rossella, additional, Sadda, Jaya, additional, Shyam, Rajalekshmy, additional, Sinha, Debasish, additional, Thompson, Debra A., additional, and Zacks, David N., additional

Published
2023
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42. The role of mitophagy in neurogenesis and neurodegeneration

Author

Boya, Patricia, Teresak, Petra, Boya, Patricia, and Teresak, Petra

Abstract

The vertebrate neural retina is a structure made up of six neuronal and one glial cell type, which arise from a pool of multipotent progenitor cells. We have previously shown that mitophagy is necessary for retinal development, since animals deficient in the protein that regulates mitophagy, NIX, show reduced numbers of retinal ganglion cells (RGC) in both the embryonic and adult retinas. In this doctoral thesis we want to further study the role of autophagy and mitophagy during retinal development, understand mitophagy levels at different stages of retinal development using MitoQC mitophagy reporter mice. The MitoQC reporter contains a tandem fusion protein (mCherryGFP) that targets the outer mitochondrial membrane (OMM). Under normal conditions, all mitochondria fluoresce in both green and red. During mitophagy, when mitochondria are transported to the lysosome, the GFP fluorescence is quenched by the acidic pH of the lysosome resulting in mitochondria marked red. Our data show that in the retina, many cell types show red dots indicative of mitophagy during different stages of embryonic development. In addition, we also show that we can induce mitophagy at different ages using pharmacological tools. Parkinson's disease (PD) is the second most prevalent neurological disease after Alzheimer's. The aetiology of Parkinson's disease is complex and unknown, although mitochondrial and lysosomal alterations play an important role. Mitophagy is impaired in patients and models with Parkinson's disease. PINK1 and Parkin are two proteins mutated in some PD patients that have a role in the control of mitophagy. Our data using the MitoQC animals injected with 6-OHDA show how mitophagy is decreased in dopaminergic neurons while the astrocytes present high levels of mitophagy., La retina neural de los vertebrados es una estructura formada por seis tipos neuronales y un tipo de célula glial, que surgen de un conjunto de progenitores multipotentes. Hemos demostrado previamente que la mitofagia es necesaria para el desarrollo de la retina, ya que los animales deficientes de NIX (proteína reguladora de mitofagia), muestran un número menor de células ganglionares tanto en la retina embrionaria como en la adulta. En la presente tesis doctoral queremos estudiar más a fondo el papel de la autofagia y la mitofagia durante el desarrollo de la retina y comprender los niveles de mitofagia en las diferentes etapas de su desarrollo. Para ello hemos utilizado los ratones reporteros de mitofagia MitoQC. El reportero MitoQC contiene una proteína de fusión en tándem (mCherryGFP) que está unida a FIS1, situada en la membrana mitocondrial externa. En condiciones normales, todas las mitocondrias emiten fluorescencia tanto en verde como en rojo. Sin embargo, durante la mitofagia, cuando las mitocondrias son transportadas al lisosoma, la fluorescencia de GFP se extingue por el pH ácido del lisosoma por lo que esa mitocondria se marca en rojo. Nuestros datos muestran que muchos tipos celulares de la retina muestran puntos rojos indicativos de mitofagia durante las diferentes etapas del desarrollo embrionario. Además, también demostramos que podemos inducir mitofagia farmacológicamente a diferentes edades. La enfermedad de Parkinson (EP) es la segunda enfermedad neurológica más prevalente después del Alzheimer. La etiología de la enfermedad de Parkinson es compleja y desconocida, aunque las alteraciones mitocondriales y lisosomales juegan un importante papel. La mitofagia, está alterada en pacientes y modelos con enfermedad de Parkinson. PINK1 y Parkin son dos proteínas mutadas en algunos pacientes con la EP que tienen un papel en el control de la mitofagia. Nuestros datos utilizando los animales MitoQC inyectados con 6-OHDA muestran cómo se ve disminuida la mitof

Published
2023

43. Supplementary Information Transcriptomics and translatomics identify a robust inflammatory gene signature in brain endothelial cells after ischemic stroke

Author

Arbaizar-Rovirosa, Maria, Gallizioli, Mattia, Lozano, Juan J., Sidorova, Julia, Pedragosa, Jordi, Figuerola, Sara, Chaparro-Cabanillas, Nerea, Boya, Patricia, Graupera, Mariona, Claret, Marc, Urra, Xabier, Planas, Anna M., Arbaizar-Rovirosa, Maria, Gallizioli, Mattia, Lozano, Juan J., Sidorova, Julia, Pedragosa, Jordi, Figuerola, Sara, Chaparro-Cabanillas, Nerea, Boya, Patricia, Graupera, Mariona, Claret, Marc, Urra, Xabier, and Planas, Anna M.

Published
2023

44. Transcriptomics and translatomics identify a robust inflammatory gene signature in brain endothelial cells after ischemic stroke

Author

Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (España), Arbaizar-Rovirosa, Maria, Gallizioli, Mattia, Lozano, Juan J., Sidorova, Julia, Pedragosa, Jordi, Figuerola, Sara, Chaparro-Cabanillas, Nerea, Boya, Patricia, Graupera, Mariona, Claret, Marc, Urra, Xabier, Planas, Anna M., Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (España), Arbaizar-Rovirosa, Maria, Gallizioli, Mattia, Lozano, Juan J., Sidorova, Julia, Pedragosa, Jordi, Figuerola, Sara, Chaparro-Cabanillas, Nerea, Boya, Patricia, Graupera, Mariona, Claret, Marc, Urra, Xabier, and Planas, Anna M.

Abstract

Vascular endothelial function is challenged during cerebral ischemia and reperfusion. The endothelial responses are involved in inflammatory leukocyte attraction, adhesion and infiltration, blood-brain barrier leakage, and angiogenesis. This study investigated gene expression changes in brain endothelial cells after acute ischemic stroke using transcriptomics and translatomics. We isolated brain endothelial mRNA by: (i) translating ribosome affinity purification, enabling immunoprecipitation of brain endothelial ribosome-attached mRNA for translatome sequencing and (ii) isolating CD31+ endothelial cells by fluorescence-activating cell sorting for classical transcriptomic analysis. Both techniques revealed similar pathways regulated by ischemia but they showed specific differences in some transcripts derived from non-endothelial cells. We defined a gene set characterizing the endothelial response to acute stroke (24h) by selecting the differentially expressed genes common to both techniques, thus corresponding with the translatome and minimizing non-endothelial mRNA contamination. Enriched pathways were related to inflammation and immunoregulation, angiogenesis, extracellular matrix, oxidative stress, and lipid trafficking and storage. We validated, by flow cytometry and immunofluorescence, the protein expression of several genes encoding cell surface proteins. The inflammatory response was associated with the endothelial upregulation of genes related to lipid storage functions and we identified lipid droplet biogenesis in the endothelial cells after ischemia. The study reports a robust translatomic signature of brain endothelial cells after acute stroke and identifies enrichment in novel pathways involved in membrane signaling and lipid storage. Altogether these results highlight the endothelial contribution to the inflammatory response, and identify novel molecules that could be targets to improve vascular function after ischemic stroke.

Published
2023

45. Bacteria-instructed B cells cross-prime naïve CD8+ T cells triggering effective cytotoxic responses

Author

Agencia Estatal de Investigación (España), Ministerio de Ciencia e Innovación (España), Ministerio de Economía, Industria y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), García-Ferreras, Raquel, Osuna-Pérez, Jesús, Ramírez-Santiago, Guillermo, Méndez-Pérez, Almudena, Acosta-Moreno, Andrés M., Del Campo, Laura, Gómez-Sánchez, María J., Iborra, Marta, Herrero-Fernández, Beatriz, González-Granado, Jose M., Sánchez-Madrid, Francisco, Carrasco, Yolanda R., Boya, Patricia, Martínez-Martín, Nuria, Veiga, Esteban, Agencia Estatal de Investigación (España), Ministerio de Ciencia e Innovación (España), Ministerio de Economía, Industria y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), García-Ferreras, Raquel, Osuna-Pérez, Jesús, Ramírez-Santiago, Guillermo, Méndez-Pérez, Almudena, Acosta-Moreno, Andrés M., Del Campo, Laura, Gómez-Sánchez, María J., Iborra, Marta, Herrero-Fernández, Beatriz, González-Granado, Jose M., Sánchez-Madrid, Francisco, Carrasco, Yolanda R., Boya, Patricia, Martínez-Martín, Nuria, and Veiga, Esteban

Abstract

In addition to triggering humoral responses, conventional B cells have been described in vitro to cross-present exogenous antigens activating naïve CD8 T cells. Nevertheless, the way B cells capture these exogenous antigens and the physiological roles of B cell-mediated cross-presentation remain poorly explored. Here, we show that B cells capture bacteria by trans-phagocytosis from previously infected dendritic cells (DC) when they are in close contact. Bacterial encounter “instructs” the B cells to acquire antigen cross-presentation abilities, in a process that involves autophagy. Bacteria-instructed B cells, henceforth referred to as BacB cells, rapidly degrade phagocytosed bacteria, process bacterial antigens and cross-prime naïve CD8 T cells which differentiate into specific cytotoxic cells that efficiently control bacterial infections. Moreover, a proof-of-concept experiment shows that BacB cells that have captured bacteria expressing tumor antigens could be useful as novel cellular immunotherapies against cancer.

Published
2023

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

Author

Beccari, Sol, primary, Sierra-Torre, Virginia, additional, Valero, Jorge, additional, Pereira-Iglesias, Marta, additional, García-Zaballa, Mikel, additional, Soria, Federico N., additional, De Las Heras-Garcia, Laura, additional, Carretero-Guillen, Alejandro, additional, Capetillo-Zarate, Estibaliz, additional, Domercq, Maria, additional, Huguet, Paloma R., additional, Ramonet, David, additional, Osman, Ahmed, additional, Han, Wei, additional, Dominguez, Cecilia, additional, Faust, Travis E., additional, Touzani, Omar, additional, Pampliega, Olatz, additional, Boya, Patricia, additional, Schafer, Dorothy, additional, Mariño, Guillermo, additional, Canet-Soulas, Emmanuelle, additional, Blomgren, Klas, additional, Plaza-Zabala, Ainhoa, additional, and Sierra, Amanda, additional

Published
2023
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