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5. 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

6. 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

7. 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

10. 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

12. 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

13. 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

14. 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

15. 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

16. 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

18. Ambra1haploinsufficiency in CD1 mice results in metabolic alterations and exacerbates age-associated retinal degeneration

Author

Ramírez-Pardo, Ignacio, primary, Villarejo-Zori, Beatriz, additional, Jiménez-Loygorri, Juan Ignacio, additional, Sierra-Filardi, Elena, additional, Alonso-Gil, Sandra, additional, Mariño, Guillermo, additional, de la Villa, Pedro, additional, Fitze, Patrick S, additional, Fuentes, José Manuel, additional, García-Escudero, Ramón, additional, Ferrington, Deborah A., additional, Gomez-Sintes, Raquel, additional, and Boya, Patricia, additional

Published
2022
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20. Ambra1 haploinsufficiency in CD1 mice results in metabolic alterations and exacerbates age-associated retinal degeneration.

Author

Ramírez-Pardo, Ignacio, Villarejo-Zori, Beatriz, Jiménez-Loygorri, Juan Ignacio, Sierra-Filardi, Elena, Alonso-Gil, Sandra, Mariño, Guillermo, de la Villa, Pedro, Fitze, Patrick S, Fuentes, José Manuel, García-Escudero, Ramón, Ferrington, Deborah A., Gomez-Sintes, Raquel, and Boya, Patricia

Subjects
GLIAL fibrillary acidic protein, RETINAL degeneration, GLUTAMINE synthetase, MACULAR degeneration, RETINAL ganglion cells, PROTEIN kinase C
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. Abbreviations : 4-HNE: 4-hydroxynonenal; AMBRA1: autophagy and beclin 1 regulator 1, AMD: age-related macular degeneration;; GCL: ganglion cell layer; GFAP: glial fibrillary acidic protein; GLUL: glutamine synthetase/glutamate-ammonia ligase; HCL: hierarchical clustering; INL: inner nuclear layer; IPL: inner plexiform layer; LC/GC-MS: liquid chromatography/gas chromatography–mass spectrometry; MA: middle-aged; MTDR: MitoTracker Deep Red; MFI: mean fluorescence intensity; NL: NH4Cl and leupeptin; Nqo: NAD(P)H quinone dehydrogenase; ONL: outer nuclear layer; OPL: outer plexiform layer; OP: oscillatory potentials; OXPHOS: oxidative phosphorylation; PCR: polymerase chain reaction; PRKC/PKCα: protein kinase C; POS: photoreceptor outer segment; RGC: retinal ganglion cells; RPE: retinal pigment epithelium; SI: sodium iodate; TCA: tricarboxylic acid. [ABSTRACT FROM AUTHOR]

Published
2023
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21. Ambra1haploinsufficiency in CD1 mice results in metabolic alterations and exacerbates age-associated retinal degeneration

Author

Ramírez-Pardo, Ignacio, Villarejo-Zori, Beatriz, Jiménez-Loygorri, Juan Ignacio, Sierra-Filardi, Elena, Alonso-Gil, Sandra, Mariño, Guillermo, de la Villa, Pedro, Fitze, Patrick S, Fuentes, José Manuel, García-Escudero, Ramón, Ferrington, Deborah A., Gomez-Sintes, Raquel, and Boya, Patricia

Abstract

ABSTRACTMacroautophagy/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+/gtmice 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.Abbreviations :4-HNE: 4-hydroxynonenal; AMBRA1: autophagy and beclin 1 regulator 1, AMD: age-related macular degeneration;; GCL: ganglion cell layer; GFAP: glial fibrillary acidic protein; GLUL: glutamine synthetase/glutamate-ammonia ligase; HCL: hierarchical clustering; INL: inner nuclear layer; IPL: inner plexiform layer; LC/GC-MS: liquid chromatography/gas chromatography–mass spectrometry; MA: middle-aged; MTDR: MitoTracker Deep Red; MFI: mean fluorescence intensity; NL: NH4Cl and leupeptin; Nqo: NAD(P)H quinone dehydrogenase; ONL: outer nuclear layer; OPL: outer plexiform layer; OP: oscillatory potentials; OXPHOS: oxidative phosphorylation; PCR: polymerase chain reaction; PRKC/PKCα: protein kinase C; POS: photoreceptor outer segment; RGC: retinal ganglion cells; RPE: retinal pigment epithelium; SI: sodium iodate; TCA: tricarboxylic acid.

Published
2023
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23. 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

24. 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

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

Author

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

Subjects
Mice, Multidisciplinary, Retinoic Acid Receptor alpha, Retinal Degeneration, Autophagy, General Physics and Astronomy, Animals, Chaperone-Mediated Autophagy, General Chemistry, Co-Repressor Proteins, General Biochemistry, Genetics and Molecular Biology, Retinitis Pigmentosa
Abstract

18 p.-8 fig., 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., This work was supported by National Institutes of Health grants AG054108, AG021904, and AG017617 (to AMC) and AG038072 (to AMC, FM, and EG), the JPB Foundation (to AMC), the Michael J. Fox Foundation (to AMC and EG), the Rainwater Charitable Foundation (to AMC and EG) and the Backus Foundation (to AMC). Chemical synthesis, NMR and MS data were in part supported by NIH awards P30 CA013330 and 1S10OD016305. Research in PB and RGS lab is funded 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 and RTI2018-098990-J-I00 to RGS. CAR was supported by T32 GM007491 and MM by T32 AG023475.

Published
2021

26. Fast and quantitative mitophagy assessment by flow cytometry using the mito -QC reporter.

Author

Jiménez-Loygorri JI, Jiménez-García C, Viedma-Poyatos Á, and Boya P

Abstract

Mitochondrial quality control is finely tuned by mitophagy, 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-FIS1 101-152 ) 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/Parkin-dependent (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 propel mitophagy research forward and accelerate the discovery of novel mitophagy modulators., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jiménez-Loygorri, Jiménez-García, Viedma-Poyatos and Boya.)

Published
2024
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