Abstract 267: High glucose-induced mitophagy limits Cardiomyocyte Injury

Abstract

Cardiovascular complications are the major cause of death among diabetic patients. Mitochondrial dysfunction has been suggested to play an important role in the pathogenesis of diabetic cardiomyopathy. Therefore, timely elimination of dysfunctional mitochondria is essential for maintaining a healthy mitochondrial network and limiting diabetic cardiac injury. This function is performed by mitophagy, a process that selectively degrades mitochondria through the autophagy-lysosome pathway. In the present study, we investigated the functional role of mitophagy in cardiomyocytes treated with high glucose, an independent risk factor for heart failure in diabetic patients. We found that mitophagy in neonatal rat ventricular myocytes was increased by high glucose (30 mM) as indicated by a novel dual fluorescent reporter as well as the co-localization of mitochondrial protein Tom20 and lysosome-associated membrane protein 1 (LAMP1). Parkin is an E3-ubiquitin ligase that positively regulates mitophagy. Parkin overexpression enhanced high glucose-induced mitophagy and attenuated cardiomyocyte injury as measured by the levels of oxidative injury, mitochondrial damage, ROS generation and cardiomyocyte death. Conversely, Parkin knockdown potentiated the toxic effects of high glucose, suggesting that mitophagy is cardioprotective under hyperglycemic conditions. In addition, high glucose increased mitochondrial fragmentation. By overexpressing or knocking down Drp1, a key regulator of mitochondrial fission, we showed that mitochondrial fragmentation was coupled with mitophagy and negatively related to the toxic effects of high glucose. Together, these findings demonstrate that high glucose induces mitochondrial fragmentation and mitophagy, which are adaptive responses that protect cardiomyocytes against high glucose toxicity. Future studies are warranted to determine if mitophagy plays a similar role in diabetic cardiac damage in vivo.