Regulation of Mitochondrial Dynamics and Cell Death by MCL-1 Matrix

MCL-1 基质对线粒体动力学和细胞死亡的调节

• 批准号: 9396120
• 负责人: Leonardo Leon
• 金额: $ 5.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9396120
• 关键词: Ablation; Adult; Affect; Apoptosis; Apoptotic; Autophagosome; BCL2 gene; Binding; Bioenergetics; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Cell Death; Cell Survival; Cells; Chimera organism; Cleaved cell; Clinical Management; Co-Immunoprecipitations; Contracts; Data; Disease; Disease Progression; Extracellular Space; Fasting; Future; Heart; Heart Diseases; Heart failure; Histology; In Situ Nick-End Labeling; In Vitro; Knowledge; Location; MCL1 gene; Mediating; Mitochondria; Mitochondrial Matrix; Mitochondrial Swelling; Monitor; Morphology; Mus; Muscle Cells; Myocardial Infarction; Myocardium; Necrosis; Organelles; Outer Mitochondrial Membrane; Oxidative Phosphorylation; Pathogenesis; Physiological; Protein Family; Proteins; Proteomics; Regulation; Role; Rupture; Site-Directed Mutagenesis; Stress; Structure; Testing; Transgenic Mice; Trichrome stain method; United States; cardiogenesis; disability; experimental study; heart function; in vivo; insight; knock-down; mitochondrial dysfunction; mutant; overexpression; response; stressor

Project Summary Cardiovascular disease is the leading cause of death and disability in the United States. Mitochondria are vital organelles for heart function because they sustain contractility by providing the heart with energy in the form of ATP through oxidative phosphorylation. Because of this, there is a strong correlation between mitochondrial dysfunction and the development of heart failure. However, the mechanism(s) of origin and precise role in disease progression are not fully understood. The anti-apoptotic BCL-2 family protein Myeloid Cell Leukemia-1 (MCL-1) is widely recognized as an important factor in programmed cell death inhibition. Interestingly, it has also been shown to be essential for maintaining mitochondrial integrity and cardiac function in the adult heart. MCL- 1 exists in two forms, one found in the outer mitochondrial membrane (MCL-1OM) and the other in the mitochondrial matrix (MCL-1Matrix). While studies have implicated MCL-1OM in regulating apoptosis, very little is known about the functional role of MCL-1Matrix. My preliminary data indicate that MCL-1Matrix can regulate mitochondrial morphology by promoting fusion of mitochondria. Furthermore, MCL-1Matrix protects mitochondria from degradation by autophagosomes in response to stress. However, the mechanism by MCL-1 exerts these functions and their functional roles in the myocardium are still unclear. The proposed project will examine the hypothesis that MCL-1Matrix promotes fusion of mitochondria to preserve bioenergetic capacity and protect them from mitophagy and necrosis during energy limiting conditions. This hypothesis will be tested through two specific aims. The first aim will delineate how MCL-1Matrix regulates mitochondrial morphology and cell survival. The second aim will evaluate the functional role of MCL-1Matrix in regulating mitochondrial morphology and function in vivo. This aim will utilize WT and cardiac specific MCL-1Matrix transgenic mice to investigate how overexpression of MCL-1Matrix affects mitochondrial structure/function and responsiveness to 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.

项目概要 心血管疾病是美国死亡和残疾的主要原因。线粒体至关重要 心脏功能的细胞器，因为它们通过为心脏提供能量来维持收缩力 ATP 通过氧化磷酸化。因此，线粒体之间存在很强的相关性。 功能障碍和心力衰竭的发展。然而，其起源机制和精确作用 疾病进展尚不完全清楚。抗凋亡 BCL-2 家族蛋白 骨髓细胞白血病-1 (MCL-1) 被广泛认为是抑制程序性细胞死亡的重要因素。有趣的是，它还 已被证明对于维持成人心脏线粒体完整性和心脏功能至关重要。 MCL- 1 以两种形式存在，一种存在于线粒体外膜 (MCL-1OM)，另一种存在于线粒体中。 线粒体基质（MCL-1Matrix）。虽然研究表明 MCL-1OM 可以调节细胞凋亡，但很少有研究表明 了解 MCL-1Matrix 的功能作用。我的初步数据表明MCL-1Matrix可以调节 通过促进线粒体融合来改变线粒体形态。此外，MCL-1Matrix 可以保护线粒体 来自自噬体响应压力而降解。然而，MCL-1 的机制发挥了这些作用 功能及其在心肌中的功能作用仍不清楚。拟议项目将审查 假设 MCL-1Matrix 促进线粒体融合以保留生物能量能力并保护它们 能量限制条件下的线粒体自噬和坏死。这个假设将通过两个特定的 目标。第一个目标将描述 MCL-1Matrix 如何调节线粒体形态和细胞存活。这 第二个目标是评估 MCL-1Matrix 在调节线粒体形态和功能中的功能作用 体内。该目标将利用 WT 和心脏特异性 MCL-1Matrix 转基因小鼠来研究过度表达如何 MCL-1Matrix 影响线粒体结构/功能以及对禁食和心肌梗塞的反应。 这些研究将为线粒体动力学、周转率之间的关系提供重要的新见解 以及内心的生存。更好地了解线粒体功能在心脏中是如何调节的 正常和疾病状况（例如心肌梗塞）将有助于未来的临床管理 心脏病。