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

项目摘要 在美国，心血管疾病是导致死亡和残疾的主要原因。线粒体是至关重要的 心脏功能的细胞器，因为它们通过以下列形式向心脏提供能量来维持收缩能力 通过氧化磷酸化的ATP。正因为如此，线粒体之间有很强的相关性 功能障碍和心力衰竭的发展。然而，机制(S)的起源和确切作用 疾病的发展还没有完全被理解。抗凋亡蛋白bcl-2家族蛋白-1 MCL-1被广泛认为是抑制细胞程序性死亡的重要因素。有趣的是，它还 已被证明是维持成人心脏线粒体完整性和心脏功能所必需的。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外膜(MCL-1OM) 线粒体基质(MCL-1Matrix)。虽然研究表明MCL-1OM参与调控细胞凋亡，但很少有 了解MCL-1Matrix的功能作用。我的初步数据表明，MCL-1矩阵可以调节 线粒体形态通过促进线粒体融合来实现。此外，MCL-1基质对线粒体有保护作用 从自噬小体对压力的反应中降解。然而，MCL-1的机制发挥了这些作用 其功能及其在心肌中的功能作用尚不清楚。拟议的项目将审查 假设MCL-1基质促进线粒体融合以保持生物能量能力并保护它们 在能量受限的条件下，从有丝分裂和坏死。这一假设将通过两个具体的 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。这个 第二个目的是评估MCL-1Matrix在调节线粒体形态和功能中的功能作用。 活着。这个目标将利用WT和心脏特异的MCL-1矩阵转基因小鼠来研究如何过度表达 MCL-1Matrix的表达影响线粒体的结构/功能以及对空腹和心肌梗死的反应性。 这些研究将为线粒体动力学和周转之间的关系提供重要的新见解 以及内心的生存。更好地了解线粒体在心脏中的功能是如何调节的 正常和疾病情况，如心肌梗死，将有助于未来的临床治疗 心脏病。

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.