Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage.

Myeloid cell leukemia-1 () is a unique antiapoptotic Bcl-2 member that is critical for mitochondrial homeostasis. Recent studies have demonstrated that 's functions extend beyond its traditional role in preventing apoptotic cell death. Specifically, data suggest that plays a regulatory role in autophagy, an essential degradation pathway involved in recycling and eliminating dysfunctional organelles. Here, we investigated whether regulates autophagy in the heart. We found that cardiac-specific overexpression of had little effect on baseline autophagic activity but strongly suppressed starvation-induced autophagy. In contrast, did not inhibit activation of autophagy during myocardial infarction or mitochondrial depolarization. Instead, overexpression of increased the clearance of depolarized mitochondria by mitophagy independent of Parkin. The increase in mitophagy was partially mediated via 's LC3-interacting regions and mutation of these sites significantly reduced -mediated mitochondrial clearance. We also found that interacted with the mitophagy receptor Bnip3 and that the interaction was increased in response to mitochondrial stress. Overall, these findings suggest that suppresses nonselective autophagy during nutrient limiting conditions, whereas it enhances selective autophagy of dysfunctional mitochondria by functioning as a mitophagy receptor.