UC San Diego

Myeloid Cell Leukemia-1 (MCL-1) is an anti-apoptotic member of the BCL-2 family of proteins that is known to antagonize intrinsic apoptotic cell death. Our lab has previously shown that the cardiac-specific ablation of MCL-1 in mice leads to severe cardiomyopathy and mitochondrial dysfunction. Surprisingly, these defects were accompanied by necrotic rather than apoptotic cell death. This suggested that MCL-1 has additional functions at the mitochondria. This study demonstrates the mechanisms by which MCL-1 sustains mitochondrial homeostasis. We

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found that overexpression of MCL-1 promotes mitochondrial perinuclear clustering. However, MCL-1 does not promote mitochondrial perinuclear clustering when Drp1 is knocked-down. Mutation of MCL-1’s BH3-domain abrogates MCL-1 mediated mitochondrial clustering. Replacing MCL-1’s BH-domains with the corresponding BH-domains from BCL-2 does not perturb this function. Additionally, overexpression of MCL-1 promotes mitochondrial clearance in response to FCCP and hypoxia. A screen of MCL-1 revealed three putative LC3-interacting region (LIR) motifs. Mitophagy was assessed when each of these three LIR motifs was mutated but no change was detected. However, mutation of MCL-1’s three LIR motifs lead to a small but significant reduction in MCL-1 mediated mitophagy. Furthermore, we demonstrated that MCL-1 can promote mitophagy independently of its anti-apoptotic function and that MCL-1-mediated mitophagy and mitochondrial aggregation occur independently of one another. Instead, we found that MCL-1 interacts with known mitophagy receptor BNIP3 during hypoxia and FCCP treatment. Thus, our data suggest that MCL-1 promotes Drp1-dependent mitochondrial fission and aggregation as well as mitochondrial clearance.