DIFFERENTIAL ROLES OF MITOPHAGY IN THE HEART UNDER FASTING AND DIABETIC CONDITIONS



Qiangrong Liang, M.D., Ph.D., New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY, USA

Mitochondria not only provide energy for cardiac contraction but also regulate the survival and death of cardiomyocytes. A pool of healthy mitochondria is maintained by several coordinated quality control mechanisms including mitophagy, a process that degrades dysfunctional mitochondria through the autophagy-lysosome pathway. Mitophagy is cardioprotective under certain conditions but may become detrimental when over-activated. In this study, we investigated the functional significance of mitophagy in the heart under either fasting or diabetic conditions. We used a novel mitophagy reporter transgenic mouse line to determine cardiac mitophagy flux in the presence and absence of lysosome inhibitors. A 24-hour fasting increased mitophagy flux in the heart, which was accompanied by increased LC3-II protein levels in the mitochondrial fractions, suggesting that 24-hour fasting enhanced mitophagy. Surprisingly, the 48-hour starvation did not further increase mitophagy. Instead, it reduced it as compared to 24-hour fasting and normal feeding. In addition, mitophagy flux was diminished in the type 1 diabetic mouse heart, which was associated with increased mitochondrial fragmentation. Overexpression of the E3 ligase Parkin, a positive regulator of mitophagy, restored mitophagy but impaired cardiac function after 48-hour fasting, suggesting that reduced mitophagy is an adaptive response essential for maintaining cardiac function during starvation. In contrast, Parkin overexpression increased mitophagy flux in the diabetic heart and attenuated diabetic cardiac injury, demonstrating a protective role of mitophagy in the diabetic heart. Collectively, these results suggest that mitophagy could be either protective or detrimental to the heart, and the functional role of cardiac mitophagy in different contexts must be individually determined.