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

Authors: ARAGONES, GEMMA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; DASURI, KALAVATHI - Tufts University; OLUKOREDE, OPEOLUWA - Tufts University; FRANCISCO, SARAH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; RENNEBURG, CAROL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; KUMSTA, CAROLINE - Sanford And Burnham Medical Research Institute; HANSEN, MALENE - Sanford And Burnham Medical Research Institute; KAGEYAMA, SHUN - Juntendo University; KOMATSU, MASAAKI - Juntendo University; ROWAN, SHELDON - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; VOLKIN, JONATHAN - Tufts University; WORKMAN, MICHAEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; YANG, WENXIN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; DAZA, PAULA - University Of Seville; RUANO, DIEGO - University Of Seville; DOMINGUEZ-MARTIN, HELENA - University Of Seville; RODRIGUEZ-NAVARRO, JOSE - Instituto Ramon Y Cajal De Investigacion Sanitaria (IRYCIS); DU, XUE-LIANG - Albert Einstein College Of Medicine; BROWNLEE, MICHAEL - Albert Einstein College Of Medicine; BEJARANO, ELOY - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; TAYLOR, ALLEN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Aging Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/15/2020
Publication Date: 11/4/2020
Citation: Aragones, G., Dasuri, K., Olukorede, O., Francisco, S.G., Renneburg, C., Kumsta, C., Hansen, M., Kageyama, S., Komatsu, M., Rowan, S., Volkin, J., Workman, M., Yang, W., Daza, P., Ruano, D., Dominguez-Martin, H., Rodriguez-Navarro, J.A., Du, X., Brownlee, M.A., Bejarano, E., Taylor, A. 2020. Autophagic receptor p62 protects against glycation-derived toxicity and enhances viability. Aging Cell. https://doi.org/10.1111/acel.13257.
DOI: https://doi.org/10.1111/acel.13257

Interpretive Summary: Aging and the consumption of high glycemic diets result in the accumulation of Advanced Glycation End Products (AGEs), which are molecules that form when sugars or their metabolites react with proteins. The accumulation of AGEs are toxic, and accumulation of high levels of AGEs predisposes individuals to a higher risk of age-related and diet-driven debilities such as age-related macular degeneration. Here we show that a specific protein called p62 that recognize these dysfunctional molecules for removal by a process called autophagy, or self eating. In this animal model study, we observed that inhibiting p62-autophagy increases AGE levels, whereas enhancing p62-autophagy decreases AGE accumulation and increases survival. This study shows for the first time the protective role of p62 against cell damage associated with aging and sugar metabolism, and we propose that targeting this process is a potential can be therapeutic to treat age and diet-related diseases.

Technical Abstract: 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 RPE is reversed by switching to lower glycemia diet. Since diminution of glycative damage is associated with reduced risk for age-related diseases, including age-related macular degeneration (AMD), cardiovascular disease, diabetes, Alzheimer's and Parkinson's, discovery of methods to limit AGEs or enhance p62-dependent autophagy offer novel potential therapeutic targets to treat AGEs-related pathologies.