Date of Award
Doctor of Philosophy (PhD)
Joseph T. Opferman, Ph.D.
Richard W. Kriwacki, Ph.D. Peter J. McKinnon, Ph.D. Rennolds S. Ostrom, Ph.D. J. Paul Taylor, Ph.D., M.D.
MCL-1 is an essential BCL-2 family member that promotes the survival of multiple cellular lineages, but its role in cardiac muscle has remained unclear. Here, we have demonstrated that cardiac-specific ablation of Mcl-1 results in a rapidly fatal, dilated cardiomyopathy preceded by loss of myofibrils and cardiac contractility, abnormal mitochondria ultrastructure, defective mitochondrial respiration, and impaired autophagy. Genetic ablation of both pro-apoptotic effectors (Bax and Bak) could largely rescue the lethality and impaired cardiac function induced by Mcl-1 deletion. However, Mcl-1-, Bax-, and Bak-deficient hearts still revealed mitochondrial ultrastructural abnormalities and displayed deficient mitochondrial respiration, and are hypersensitive to chronic isoproterenol challenge. Together, these studies indicate that MCL-1 functions beyond merely blocking cardiomyocyte death and suggest that in myocardium, MCL-1 also facilitates normal mitochondrial function. These findings are important, as overexpression MCL-1 in the heart could be a potential strategy to overcome cardiac injury and promote efficient mitochondrial function and would be beneficial to human health. Of equal importance, specific MCL-1-inhibiting therapeutics that has been proposed to treat cancer may result in unexpected cardiac toxicity; it may be necessary to take this possible side effect into account during MCL-1 inhibitor development.
Wang, Xi , "The Role of MCL-1 in the Heart: Gateway from Life to Death" (2014). Theses and Dissertations (ETD). Paper 368. http://dx.doi.org/10.21007/etd.cghs.2014.0342.