Drp1-dependent mitochondrial autophagy plays a protective role against pressure-overload-induced mitochondrial dysfunction and heart failure

heart failure after TAC. Injection of Tat-Beclin 1, a potent inducer of autophagy, but not control peptide, on day 7 after TAC, partially rescued mitochondrial autophagy and attenuated mitochondrial dysfunction and heart failure induced by overload. Haploinsufficiency of either drp1 or beclin 1 prevented the rescue by Tat-Beclin 1, suggesting that its effect is mediated in part through autophagy, including mitochondrial autophagy. Conclusions —Mitochondrial autophagy is transiently activated and then downregulated in the mouse heart in response to pressure overload. Downregulation of mitochondrial autophagy plays an important role in mediating the development of mitochondrial dysfunction and heart failure, whereas restoration of mitochondrial autophagy attenuates dysfunction in the heart during pressure overload. ( Circulation . 2016;133:1249-1263. DOI: 10.1161/CIRCULATIONAHA.115.020502.) rapidly through depolarization of the mitochondrial membrane potential and causes deterioration of the function of healthy mitochondria. Thus, cardiomyocytes possess robust quality control mechanisms, and autophagy, which degrades protein and organelles through lysosomes, is a major mechanism for the elimination of dysfunctional mitochondria. In this study, we show that both general autophagy and a mitochondria-specific form of autophagy (mitochondrial autophagy) are downregulated after pressure overload and that mitochondrial dysfunction develops only after mitochondrial autophagy is downregulated. Mitochondrial autophagy was induced in response to pressure overload through a mechanism dependent on Drp1, a protein known to mediate mitochondrial fission. Treatment of animals with Tat-Beclin 1 peptide, known to stimulate autophagy through mobilization of endogenous Beclin 1, a protein essential for autophagy, increased the level of mitochondrial autophagy in the heart and partially rescued the animals from the development of pressure overload–induced heart failure. These results suggest that interventions to restore the level of mitochondrial autophagy should be considered for potential treatment for patients with heart failure.