410-P: An Impaired Mitophagy-Lysosome System Contributes to Hyperglycemia Cardiotoxicity

2019 
Mitochondrial dysfunction plays an important role in diabetic heart damage. A healthy pool of mitochondria is maintained through a number of quality control mechanisms including mitophagy that degrades dysfunctional mitochondria through the lysosome. In the present study, we investigated the function of mitophagy-lysosome system in the diabetic heart and in cardiomyocytes cultured under high glucose. Streptozotocin-induced diabetes initiated mitophagy in the mouse heart but did not lead to its completion in the lysosome. Overexpression of the E3 ligase Parkin accelerated mitophagy flux and reduced diabetic cardiac injury. In contrast, Parkin gene deletion had the opposite effects, suggesting an essential role for mitophagy in maintaining cardiac homeostasis in diabetes. Lysophagy is the degradation of injured lysosomes by healthy lysosomes which is extremely important for all forms of autophagy. Using a novel dual fluorescent lysosome reporter, we showed that diabetes triggered lysosomal injury but reduced lysophagy flux, leading to the accumulation of injured lysosomes and the release of lysosomal enzymes such as cathepsin D. High glucose had similar effects in cultured cardiomyocytes. Enhancing lysophagy not only reduced high glucose toxicity but also accelerated mitophagy flux. Together, these results suggest that lysosomal dysfunction accounts at least partially for the reduced mitophagy flux and increased diabetic heart damage and that restoring lysosomal function may enhance mitochondrial quality control and reduce hyperglycemia cardiotoxicity. Disclosure S. Kobayashi: None. Y. Huang: None. T. Kobayashi: None. C. Li: None. F. Cai: None. Q. Liang: None. Funding National Institutes of Health
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