Abstract 375: MCL-1 Regulates Mitochondrial Dynamics and Mitophagy

Abstract

The anti-apoptotic BCL-2 family protein Myeloid Cell Leukemia-1 (MCL-1) is essential for maintaining mitochondrial integrity and cardiac function in the adult heart. Recently, we reported that cardiac-specific deletion of MCL-1 in mice leads to rapid mitochondrial dysfunction, hypertrophy, and lethal cardiomyopathy. Surprisingly, MCL-1 ablation does not result in apoptotic cell death, but rather cells show signs of mitochondrial deterioration and necrotic cell death. This suggests that in addition to its anti-apoptotic role, MCL-1 has unidentified roles in maintaining mitochondrial function in cardiac myocytes. MCL-1 exists in two distinct locations in myocytes: one form is localized to the outer mitochondrial membrane (MCL-1 OM ) and a shorter cleaved form exists in the mitochondrial matrix (MCL-1 Matrix ). Interestingly, overexpression of MCL-1 WT or MCL-1 OM , but not MCL-1 Matrix , leads to translocation of Drp1 to mitochondria, which correlates with fission and perinuclear aggregation of mitochondria. We also found that Drp1 co-immunoprecipitates with MCL-1 in heart lysates and that MCL-1-deficient hearts lack mitochondrial Drp1. Additionally, the interaction between Drp1 and MCL-1 and mitochondrial fission increase in response to serum starvation in neonatal myocytes. This suggests that MCL-1 OM recruits Drp1 to mitochondria to induce fission. Since there is a strong link between mitochondrial fission and degradation, we examined the effect of MCL-1 on mitophagy. Parkin is an E3 ubiquitin ligase that plays an important role in mitophagy. MEFs, which lack detectable Parkin, do not efficiently clear their depolarized mitochondria in response to FCCP treatment. However, overexpression of Parkin or MCL-1 increased the efficiency of mitophagy in MEFs in response to FCCP treatment. MCL-1-mediated mitophagy is abrogated in autophagy-deficient Atg5 -/- MEFs, confirming that the clearance occurs via enhanced autophagy. Thus, our data suggest that MCL-1 OM has dual actions in coordinating Drp1-mediated fission and mitophagy, which allows for more efficient removal of damaged mitochondria.