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Autophagic receptor p62 protects against glycation‐derived toxicity and enhances viability

Diabetes and metabolic syndrome are associated with the typical American high glycemia diet and result in accumulation of high levels of advanced glycation end products (AGEs), particularly upon aging. AGEs form when sugars or their metabolites react with proteins. Associated with a myriad of age‐re...

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Autores principales: Aragonès, Gemma, Dasuri, Kalavathi, Olukorede, Opeoluwa, Francisco, Sarah G., Renneburg, Carol, Kumsta, Caroline, Hansen, Malene, Kageyama, Shun, Komatsu, Masaaki, Rowan, Sheldon, Volkin, Jonathan, Workman, Michael, Yang, Wenxin, Daza, Paula, Ruano, Diego, Dominguez‐Martín, Helena, Rodríguez‐Navarro, José Antonio, Du, Xue‐Liang, Brownlee, Michael A., Bejarano, Eloy, Taylor, Allen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681057/
https://www.ncbi.nlm.nih.gov/pubmed/33146912
http://dx.doi.org/10.1111/acel.13257
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author Aragonès, Gemma
Dasuri, Kalavathi
Olukorede, Opeoluwa
Francisco, Sarah G.
Renneburg, Carol
Kumsta, Caroline
Hansen, Malene
Kageyama, Shun
Komatsu, Masaaki
Rowan, Sheldon
Volkin, Jonathan
Workman, Michael
Yang, Wenxin
Daza, Paula
Ruano, Diego
Dominguez‐Martín, Helena
Rodríguez‐Navarro, José Antonio
Du, Xue‐Liang
Brownlee, Michael A.
Bejarano, Eloy
Taylor, Allen
author_facet Aragonès, Gemma
Dasuri, Kalavathi
Olukorede, Opeoluwa
Francisco, Sarah G.
Renneburg, Carol
Kumsta, Caroline
Hansen, Malene
Kageyama, Shun
Komatsu, Masaaki
Rowan, Sheldon
Volkin, Jonathan
Workman, Michael
Yang, Wenxin
Daza, Paula
Ruano, Diego
Dominguez‐Martín, Helena
Rodríguez‐Navarro, José Antonio
Du, Xue‐Liang
Brownlee, Michael A.
Bejarano, Eloy
Taylor, Allen
author_sort Aragonès, Gemma
collection PubMed
description Diabetes and metabolic syndrome are associated with the typical American high glycemia diet and result in accumulation of high levels of advanced glycation end products (AGEs), particularly upon aging. AGEs form when sugars or their metabolites react with proteins. Associated with a myriad of age‐related diseases, AGEs accumulate in many tissues and are cytotoxic. To date, efforts to limit glycation pharmacologically have failed in human trials. Thus, it is crucial to identify systems that remove AGEs, but such research is scanty. Here, we determined if and how AGEs might be cleared by autophagy. Our in vivo mouse and C. elegans models, in which we altered proteolysis or glycative burden, as well as experiments in five types of cells, revealed more than six criteria indicating that p62‐dependent autophagy is a conserved pathway that plays a critical role in the removal of AGEs. Activation of autophagic removal of AGEs requires p62, and blocking this pathway results in accumulation of AGEs and compromised viability. Deficiency of p62 accelerates accumulation of AGEs in soluble and insoluble fractions. p62 itself is subject to glycative inactivation and accumulates as high mass species. Accumulation of p62 in retinal pigment epithelium is reversed by switching to a lower glycemia diet. Since diminution of glycative damage is associated with reduced risk for age‐related diseases, including age‐related macular degeneration, cardiovascular disease, diabetes, Alzheimer's, and Parkinson's, discovery of methods to limit AGEs or enhance p62‐dependent autophagy offers novel potential therapeutic targets to treat AGEs‐related pathologies.
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spelling pubmed-76810572020-11-27 Autophagic receptor p62 protects against glycation‐derived toxicity and enhances viability Aragonès, Gemma Dasuri, Kalavathi Olukorede, Opeoluwa Francisco, Sarah G. Renneburg, Carol Kumsta, Caroline Hansen, Malene Kageyama, Shun Komatsu, Masaaki Rowan, Sheldon Volkin, Jonathan Workman, Michael Yang, Wenxin Daza, Paula Ruano, Diego Dominguez‐Martín, Helena Rodríguez‐Navarro, José Antonio Du, Xue‐Liang Brownlee, Michael A. Bejarano, Eloy Taylor, Allen Aging Cell Original Articles Diabetes and metabolic syndrome are associated with the typical American high glycemia diet and result in accumulation of high levels of advanced glycation end products (AGEs), particularly upon aging. AGEs form when sugars or their metabolites react with proteins. Associated with a myriad of age‐related diseases, AGEs accumulate in many tissues and are cytotoxic. To date, efforts to limit glycation pharmacologically have failed in human trials. Thus, it is crucial to identify systems that remove AGEs, but such research is scanty. Here, we determined if and how AGEs might be cleared by autophagy. Our in vivo mouse and C. elegans models, in which we altered proteolysis or glycative burden, as well as experiments in five types of cells, revealed more than six criteria indicating that p62‐dependent autophagy is a conserved pathway that plays a critical role in the removal of AGEs. Activation of autophagic removal of AGEs requires p62, and blocking this pathway results in accumulation of AGEs and compromised viability. Deficiency of p62 accelerates accumulation of AGEs in soluble and insoluble fractions. p62 itself is subject to glycative inactivation and accumulates as high mass species. Accumulation of p62 in retinal pigment epithelium is reversed by switching to a lower glycemia diet. Since diminution of glycative damage is associated with reduced risk for age‐related diseases, including age‐related macular degeneration, cardiovascular disease, diabetes, Alzheimer's, and Parkinson's, discovery of methods to limit AGEs or enhance p62‐dependent autophagy offers novel potential therapeutic targets to treat AGEs‐related pathologies. John Wiley and Sons Inc. 2020-11-04 2020-11 /pmc/articles/PMC7681057/ /pubmed/33146912 http://dx.doi.org/10.1111/acel.13257 Text en © 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Aragonès, Gemma
Dasuri, Kalavathi
Olukorede, Opeoluwa
Francisco, Sarah G.
Renneburg, Carol
Kumsta, Caroline
Hansen, Malene
Kageyama, Shun
Komatsu, Masaaki
Rowan, Sheldon
Volkin, Jonathan
Workman, Michael
Yang, Wenxin
Daza, Paula
Ruano, Diego
Dominguez‐Martín, Helena
Rodríguez‐Navarro, José Antonio
Du, Xue‐Liang
Brownlee, Michael A.
Bejarano, Eloy
Taylor, Allen
Autophagic receptor p62 protects against glycation‐derived toxicity and enhances viability
title Autophagic receptor p62 protects against glycation‐derived toxicity and enhances viability
title_full Autophagic receptor p62 protects against glycation‐derived toxicity and enhances viability
title_fullStr Autophagic receptor p62 protects against glycation‐derived toxicity and enhances viability
title_full_unstemmed Autophagic receptor p62 protects against glycation‐derived toxicity and enhances viability
title_short Autophagic receptor p62 protects against glycation‐derived toxicity and enhances viability
title_sort autophagic receptor p62 protects against glycation‐derived toxicity and enhances viability
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681057/
https://www.ncbi.nlm.nih.gov/pubmed/33146912
http://dx.doi.org/10.1111/acel.13257
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