RT Journal Article
T1 Autophagic receptor p62 protects against glycation-derived toxicity and enhances viability.
A1 Aragones, Gemma
A1 Dasuri, Kalavathi
A1 Olukorede, Opeoluwa
A1 Francisco, Sarah G
A1 Renneburg, Carol
A1 Kumsta, Caroline
A1 Hansen, Malene
A1 Kageyama, Shun
A1 Komatsu, Masaaki
A1 Rowan, Sheldon
A1 Volkin, Jonathan
A1 Workman, Michael
A1 Yang, Wenxin
A1 Daza, Paula
A1 Ruano, Diego
A1 Dominguez-Martin, Helena
A1 Rodriguez-Navarro, Jose Antonio
A1 Du, Xue-Liang
A1 Brownlee, Michael A
A1 Bejarano, Eloy
A1 Taylor, Allen
K1 aging
K1 autophagy
K1 glycative stress
K1 p62
K1 proteotoxicity
AB 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.
PB Wiley-Blackwell Publishing Ltd.
YR 2020
FD 2020-11-22
LK http://hdl.handle.net/10668/16541
UL http://hdl.handle.net/10668/16541
LA en
NO Aragonès G, Dasuri K, Olukorede O, Francisco SG, Renneburg C, Kumsta C, et al. Autophagic receptor p62 protects against glycation-derived toxicity and enhances viability. Aging Cell. 2020 Nov;19(11):e13257.
NO Funding was provided by NIH R01EY021212, R01EY028559, and R01EY026979 (to AT), USDA NIFA 2016-08885 (to AT and SR), USDA 8050-51000-089-01S (to AT), Thome Memorial Foundation (to AT), BrightFocus Foundation (to SR), NIH R21AG058038 (to CK), NIH R01AG028664 (to MH), MINECO SAF 2016 78666-R ( to JARN and EB), and a grant from this Human Nutrition Research Center on Aging (to EB). This material is based upon work supported by the U.S. Department of Agriculture—Agricultural Research Service (ARS), under Agreement No. 58-1950-4-003. The authors declare no competing financial interests. The authors are grateful for review of this manuscript by Dr. Weinberg and Dr. Musil.
DS RISalud
RD Apr 8, 2025