UC San Diego

Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic BCL-2 protein that is upregulated in several human cancers. MCL- 1 is also highly expressed in myocardium, but its function in myocytes has not been investigated. To study this function, I generated inducible, cardiomyocyte-specific Mcl-1 knockout mice and found that loss of MCL-1 in the adult heart led to rapid cardiomyopathy, cardiac hypertrophy, fibrosis with loss of myocytes, and early mortality. Although MCL-1 is known to inhibit apoptosis, this process was not activated in MCL-1-deficient hearts. Instead, ultrastructural analysis revealed disorganized sarcomeres and swollen mitochondria in myocytes. I found that loss of MCL-1 led to mitochondrial rupture, LDH release, and cardiac inflammation that indicate myocardial necrosis. Mitochondria isolated from MCL-1-deficient hearts also exhibited reduced respiration, impaired oxidative phosphorylation enzyme activity, and reduced Ca²⁺-mediated swelling. Taken together, these data are consistent with mitochondrial damage and opening of the mitochondrial permeability transition pore (mPTP). Double knockout mice lacking MCL-1 and cyclophilin D, an essential regulator of the mPTP, exhibited delayed progression to heart failure and extended survival. Autophagy is normally enhanced in response to myocardial stress, but induction of autophagy was impaired in MCL-1- deficient hearts. Accordingly, I found that ablation of MCL-1 led to accumulation of autophagic substrates in cardiac tissue. In addition, the loss of MCL-1 compromised mitochondrial turnover in myocardium by disrupting PINK1/ Parkin-mediated mitophagy. Finally, my studies show that MCL-1 and Parkin do not directly interact in the heart. These data demonstrate that MCL-1 is essential for myocardial homeostasis and induction of autophagy in cardiac myocytes. My dissertation also raises concerns about potential cardiotoxicity for chemotherapeutics that target MCL-1