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Regulation of Cardiac Death and Energy Metabolism by MCL-1

MCL-1 对心源性死亡和能量代谢的调节

基本信息

批准号：
8886812
负责人：
JOSEPH T. OPFERMAN
金额：
$ 47.93万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-07 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8886812
关键词：
Adult Apoptosis Apoptotic Attenuated BAX gene BCL2 gene Biochemical Genetics Cardiac Cardiac Death Cardiac Myocytes Cardiomyopathies Cardiotoxicity Cardiovascular system Cell Death Cell Line Cessation of life Chronic Data Ectopic Expression Energy Metabolism Exhibits Family member Fibrosis Genetic Models Glucose Glycolysis Goals Heart Heart failure In Vitro Isoproterenol Lead Mediating Membrane Metabolic Metabolism Mitochondria Modeling Morbidity - disease rate Mus Myocardial Myocardial Contraction Necrosis Outer Mitochondrial Membrane Physiology Positioning Attribute Process Production Regulation Research Respiration Role Staging Stress Structural defect Testing Therapeutic Toxic effect United States United States National Institutes of Health Work cancer therapy experience fatty acid oxidation genetic approach in vivo inhibitor/antagonist innovation mitochondrial dysfunction mortality mutant novel therapeutics overexpression oxidation prevent public health relevance self-renewal

项目摘要

DESCRIPTION (provided by applicant): Cardiomyocyte-specific deletion of anti-apoptotic Mcl-1 results in a fatal cardiomyopathy preceded by loss of cardiac contractility, abnormal mitochondrial ultrastructure, and impaired respiration. Co-deletion of the pro- apoptotic effectors Bax and Bak rescued the lethality and impaired cardiac function induced by Mcl-1-deletion; however, mitochondria from Mcl-1, Bax, and Bak-deficient (TKO) hearts still exhibited ultra-structural abnormalities and deficient mitochondrial respiration. These data suggest that MCL-1 facilitates normal mitochondrial function and promotes cardiomyocyte survival in cardiomyocytes. We have identified that MCL-1 resides in distinct mitochondrial localizations exhibiting separable functions: outer mitochondrial membrane (OMM)-localized MCL-1 inhibits cell death and matrix-localized MCL-1 promotes normal mitochondrial physiology. However, how these forms of MCL-1 contribute to regulating cardiomyocyte survival and mitochondrial function remains unclear. Our central hypothesis is that in cardiomyocytes MCL-1 functions at separable mitochondrial localizations: the outer membrane form prevents apoptosis and the matrix-localized form maintains efficient cardiomyocyte mitochondrial function by supporting energy metabolism. We propose to use biochemical and genetic approaches to tackle the following significant and innovative questions: Aim 1: How does MCL-1 regulate the death of cardiomyocytes? Inducible deletion of Mcl-1 in adult hearts leads to the loss of cardiomyocytes and fibrosis. Our working hypothesis is that OMM-localized MCL-1 is required to promote cardiomyocyte survival by preventing BAX/BAK-mediated apoptosis. Aim 2: How do MCL- 1's different localizations contribute to regulating mitochondrial function in cardiomyocytes? MCL-1 loss leads to mitochondrial dysfunction even when Bax and Bak are deleted and causes defective fatty acid (FA) oxidation in model cell lines. We postulate that in cardiomyocytes matrix-localized MCL-1 facilitates normal mitochondrial FA oxidation. Aim 3. Can ectopic MCL-1 expression inhibit cardiac failure by preventing death and maintaining normal cardiomyocyte energy metabolism? In the advanced stages of heart failure myocardial energy metabolism shifts from primarily FA oxidation to increased glycolysis and there is evidence of cardiomyocyte death. Since, MCL-1 blocks both cell death and modulates cardiomyocyte mitochondrial function, we hypothesize that overexpression of MCL-1 targeted mutants will reveal that MCL-1 not only blocks cardiomyocyte death, but helps maintain cardiomyocyte energy metabolism. We are ideally positioned to carry out the proposed studies as we possess expertise in studying MCL-1's diverse functions in vitro and in vivo, have developed essential mouse genetic models to support the studies, and are experienced in characterizing MCL-1's role in cardiac function. At the end of this study, we will have a new understanding of how MCL-1's diverse functions may be utilized to promote cardiomyocyte survival and may reveal ways to avoid potential cardiac toxicities associated with chemotherapeutic inhibition of MCL-1.