| 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. |
