Date of Award

12-2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Research Advisor

Joseph T. Opferman, Ph.D.

Committee

Richard W. Kriwacki, Ph.D. Peter J. McKinnon, Ph.D. Rennolds S. Ostrom, Ph.D. J. Paul Taylor, Ph.D., M.D.

Keywords

apoptosis, BCL-2, heart failure, MCL-1, mitochondria

Abstract

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.

DOI

10.21007/etd.cghs.2014.0342

Comments

One year embargo expired December 2015

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