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 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.
Highlights
Americans consume very high glycemic diets, and the trend toward consuming these diets is increasing throughout the world
It is presently unknown 1) if the clearance of advanced glycation end products (AGEs) is impacted by crosstalk between the ubiquitin-proteasome system (UPS) and autophagy, 2) if different pools of AGEs are differentially targeted to each pathway, and 3) if upregulating proteolytic pathways increases clearance of AGEs to benefit cell and organismic viability in the face of glycative stress
We previously found that lysosomal activity was involved in clearance of AGEs, some of which were ubiquitinated, but the mechanism of this process remained an enigma (Uchiki et al, 2012). p62 is an autophagic receptor that recruits ubiquitinated substrates to autophagosomes for subsequent degradation in the autolysosome (Pankiv et al, 2007)
Summary
Americans consume very high glycemic diets, and the trend toward consuming these diets is increasing throughout the world. The UPS and autophagy cooperate functionally, and the deficiency of one of these pathways can trigger the upregulation of the other route (Gavilan et al, 2015; Ji & Kwon, 2017) The function of these degradative pathways declines with age, contributing to the intracellular accumulation of proteinaceous aggregates and dysfunctional organelles in aged tissues (Mizushima et al, 2008). It is presently unknown 1) if the clearance of AGEs is impacted by crosstalk between the UPS and autophagy, 2) if different pools of AGEs are differentially targeted to each pathway, and 3) if upregulating proteolytic pathways increases clearance of AGEs to benefit cell and organismic viability in the face of glycative stress. We show for the first time a protective role for p62 against glycation-derived toxicity and identify this autophagic receptor as a novel potential therapeutic target to treat AGEs-related pathologies
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