Abstract 280: MCL-1 Matrix Promotes Mitochondrial Fusion and Protects Against TAC Induced Hypertrophy

Abstract

The anti-apoptotic BCL-2 protein MCL-1 is highly expressed in the myocardium, and we have previously found that deletion in cardiomyocytes leads to mitochondrial dysfunction and rapid development of heart failure. MCL-1 exists both in the outer mitochondrial membrane (MCL-1 OM ) and in the mitochondrial matrix (MCL-1 Matrix ). Because Mcl-1 -/- mice lack both MCL-1 Matrix and MCL-1 OM , the functional role of each form remains unknown. While studies have implicated MCL-1 OM in regulating apoptosis, very little is known about the functional role of MCL-1 Matrix . Here, we show that mitochondria are responsive to alterations in cellular metabolism, and culturing mouse embryonic fibroblasts (MEFs) in “oxidative” media containing galactose or acetoacetate led to a significant increase in the MCL-1 Matrix /MCL-1 OM ratio and elongation of mitochondria. We confirmed that MCL-1 Matrix overexpression promoted mitochondrial fusion and reduced maximal mitochondrial respiration under baseline conditions. Interestingly, the elongated mitochondria were initially protected against FCCP-induced fission and mitophagy. However, prolonged exposure to FCCP resulted in abrogation of MCL-1 Matrix import. Accumulation of MCL-1 Matrix on the outer membrane led to its degradation and subsequent induction of mitophagy. Furthermore, to investigate its functional role in the heart, we generated cardiac specific MCL-1 Matrix (αMHC-MCL-1 Matrix ) transgenic mice. The mice show no differences in cardiac structure and function compared to wild-type litter mates at 3 months. However, ultrastructural analysis revealed the presence of enlarged mitochondria in myocytes from αMHC-MCL-1 Matrix mice. Finally, we subjected WT and αMHC-MCL-1 Matrix mice to transverse aortic constriction (TAC) and we found that αMHC-MCL-1 Matrix mice had reduced heart weight to body weight (HW/BW) ratio and decreased expression of hypertrophy markers ANF, BNP, and MHC-β at two weeks post-TAC compared to WT. Thus, our studies indicate that cardiac overexpression of MCL-1 Matrix promotes mitochondrial enlargement in myocytes and alleviates stress placed on the heart during pressure overload.