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MCL-1 is a critical regulator of mitochondrial dynamics and function in myocytes

MCL-1 是肌细胞线粒体动力学和功能的关键调节因子

基本信息

批准号：
9812170
负责人：
Asa B. Gustafsson
金额：
$ 7.2万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9812170
关键词：
Affect Apoptosis Apoptotic Autophagocytosis Autophagosome BCL-2 Protein Bioenergetics Calcium Cardiac Cardiac Myocytes Cardiovascular Diseases Cell Death Cell physiology Cells Cellular biology Clinical Management Contracts DNA Damage Data Defect Development Disease Disease Progression Ensure Environment Excision Fasting Future Goals Health Heart Heart Diseases Heart failure Homeostasis Impairment In Vitro Knowledge Location MCL1 gene Mediating Membrane Potentials Mitochondria Mitochondrial Matrix Molecular Molecular Biology Monitor Morphology Muscle Cells Myocardial Infarction Myocardium Necrosis Nutrient Outer Mitochondrial Membrane Oxidative Phosphorylation Pathogenesis Physiological Play Proteins Proteomics Reactive Oxygen Species Research Role Site-Directed Mutagenesis Stress Structure Testing base cardiogenesis in vivo insight mitochondrial dysfunction mitochondrial membrane mortality mouse model new therapeutic target overexpression parkin gene/protein preservation prevent programs receptor recruit response

项目摘要

Project Summary While mitochondrial dysfunction is evident in the failing heart, its precise role in disease progression is unclear and the mechanism(s) of its origin is not well understood. Mitochondria play a key role in many cellular processes, including oxidative phosphorylation, metabolite synthesis and calcium storage. They are also important regulators of cell death and monitor changes in the intracellular environment such as presence of reactive oxygen species and DNA damage. The BCL-2 proteins play a key role in regulating mitochondrial membrane permeabilization and apoptosis. We recently discovered that the anti-apoptotic BCL-2 protein MCL-1 is critical for normal mitochondrial function and cardiac homeostasis. Loss of MCL-1 in cardiac myocytes leads to rapid mitochondrial dysfunction, development of heart failure, and early mortality. Surprisingly, MCL-1 deficient myocytes display signs of necrosis rather than apoptosis as would be expected, suggesting that besides its anti- apoptotic role, MCL-1 has an essential but yet unidentified role in maintaining mitochondrial function in cardiac myocytes. We have also found that MCL-1 exists both in the outer mitochondrial membrane (MCL-1OM) and in the mitochondrial matrix (MCL-1Matrix) in the heart. While a study has implicated MCL-1OM in regulating apoptosis, the function of MCL-1Matrix is still unknown. Based on our preliminary data, we propose to study the hypothesis that MCL-1 has a dual role in maintaining cardiac mitochondrial function and health that is dependent on its mitochondrial location: MCL-1OM facilitates mitochondrial fission and mitophagy of aberrant mitochondria to prevent activation of unnecessary apoptosis, whereas MCL-1Matrix promotes mitochondrial fusion to preserve bioenergetic capacity and protect against autophagosomal degradation during nutrient limiting conditions. This hypothesis will be tested with three specific aims. In Specific Aim 1, we will characterize the role of MCL-1Matrix in regulating mitochondrial fusion, function, turnover and survival. In Specific Aim 2, we will delineate the role of MCL-1OM in regulating mitochondrial fission and turnover. We will determine if MCL-1OM interacts with Drp1 to promote asymmetrical fission and removal of damaged mitochondria and whether this is part of its pro-survival function. Finally, in Specific Aim #3, we will investigate whether MCL-1OM also functions as a receptor for LC3 to drive selective degradation of mitochondrial by autophagosomes. We will utilize both isolated cardiac myocytes and genetically modified mouse models combined with proteomics, cell and molecular biology to uncover the bi- functional roles of MCL-1OM and MCL-1Matrix in myocytes under baseline conditions and in response to challenge (fasting and myocardial infarction). These studies will provide important new insights into the relationship between mitochondrial dynamics, turnover and survival in the heart. A better understanding of how mitochondrial function is regulated in the heart under normal and disease conditions such as myocardial infarct will contribute towards future clinical management of heart disease.

项目总结