Linking cell death and mitochondrial quality control mechanisms in heart disease

将心脏病中的细胞死亡和线粒体质量控制机制联系起来

• 批准号: 9032529
• 负责人: Gerald W. Dorn
• 金额: $ 51.5万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032529
• 关键词: Acute; Adult; Animals; Apoptosis; Binding; Biogenesis; Biology; Blood Circulation; Cardiac; Cardiac Myocytes; Cell Death; Cells; Cessation of life; Collaborations; Complex; Data; Disease; Figs - dietary; Heart; Heart Diseases; Heart failure; In Vitro; Individual; Infarction; Injury; Ischemia; Lead; Link; Literature; Mediating; Mediator of activation protein; Mitochondria; Modeling; Molecular; Molecular Conformation; Necrosis; Pathogenesis; Physiological; Postdoctoral Fellow; Process; Production; Quality Control; Reperfusion Therapy; Research; Research Assistant; Role; Signal Transduction; Structure; System; Testing; Work; base; experience; genetic manipulation; heart cell; in vivo; innovation; mortality; parkin gene/protein; prevent; professor; public health relevance; research study

 DESCRIPTION (provided by applicant): Mitochondria engage in multiple fundamental processes including biogenesis, fission/fusion, mitophagy, and cell death - in addition to their role as ATP generators in the cell. These processes are complex, and for this reason, have been largely studied in isolation. Yet, it is clear that they overlap substantially at the molecula level, functionally, and with respect to their roles in disease. In this application, we propose experiments that bi-directionally connect Bax, a central mediator of cardiomyocyte death, with Parkin, an important activator of mitophagy in cardiomyocytes. Using genetic manipulations, we have found unexpectedly that endogenous levels of Bax in healthy cells suppress mitophagy. We have observed this in adult cardiomyocytes in vitro and in the heart in vivo. We postulate that this is a physiological mechanism that restrains inappropriate or excessive elimination of mitochondria, a situation that would be deleterious to cardiomyocytes, which are highly dependent on ATP. We will elucidate the mechanism, which may involve an interaction between Bax and Parkin, and test the functional significance in vitro and in vivo. The fact that Bax and Parkin interact raises the reciprocal question: What might Parkin be doing to Bax in the heart? Previous work in non-cardiac systems has shown that Parkin inhibits Bax translocation to mitochondria during cell death, but the mechanism has not been elucidated. Parkin is known to inhibit cardiomyocyte death in vitro, and deletion of Parkin in vivo markedly exacerbates post-infarct remodeling, heart failure, and mortality. These effects have been assumed to be mediated solely through Parkin-stimulated mitophagy. Given the directness of the connection between Bax and cardiomyocyte apoptosis and necrosis, however, we challenge that view and hypothesize that Parkin protects the heart primarily through its inhibition of Bax. We will test ths hypothesis and delineate the molecular mechanism by which Parkin inhibits Bax. Accordingly, the over-arching hypothesis of this project is that Bax and Parkin antagonize each other for the benefit of cardiomyocytes: The binding of Bax, likely in its cell death-inactive conformation, to Parkin inhibits Parkin-mediated mitophagy to prevent mitochondrial depletion. Conversely, the Bax-Parkin interaction inhibits Bax, likely through interfering with its transition to its active conformation, thereby inhibiting cardiomyocyte apoptosis and necrosis. This is an MPI application that brings together the expertise of Richard Kitsis (cardiomyocyte death) and Gerald Dorn (cardiac mitophagy). This research is highly significant as it will stimulate the field to consider and investigate connections between individual mitochondrial processes, such as cell death and mitophagy. In addition, it will lead to a reconsideration of the primary mechanism by which Parkin protects the heart. The work is also highly innovative because most of the concepts and relationships have not been previously considered. Through this research, we will achieve a better understanding of the pathogenesis of acute cardiac injury during ischemia/reperfusion and post-infarct remodeling.

 描述（由应用程序提供）：线粒体还参与了多个基本过程，包括生物发生，裂变/融合，线粒体和细胞死亡 - 除了它们在细胞中的ATP发电机的作用外。这些过程很复杂，因此，在很大程度上是孤立研究的。但是，很明显，它们在功能上以及在疾病中的作用方面在分子水平上实质上重叠。在此应用中，我们提出了实验，即双向将BAX（心肌细胞死亡的中心介体）与心肌细胞中线粒体的重要激活剂帕金（Parkin）联系起来。使用遗传操纵，我们意外地发现，健康细胞中的内源性BAX抑制线粒体。我们已经在体外和心脏的成年心肌细胞中观察到了这一点。我们假设这是一种物理机制，可以限制不适当或超出线粒体的消除，这种情况将被删除为心肌细胞，高度依赖于ATP。我们将阐明该机制，这可能涉及Bax和Parkin之间的相互作用，并在体外和体内测试功能意义。 Bax和Parkin互动的事实提出了一个相互的问题：Parkin在心脏中会做些什么？非心脏系统中的先前工作表明，帕金在细胞死亡期间抑制了Bax易位向线粒体，但尚未阐明该机制。众所周知，Parkin会在体外抑制心肌细胞死亡，而在体内删除了帕金，显着加剧了侵袭后的重塑，心力衰竭和死亡率。这些作用已被认为是仅通过帕金刺激的线粒体介导的。但是，鉴于Bax和心肌细胞凋亡与坏死之间的联系的直接性，我们挑战了这种观点和假设，即Parkin主要通过抑制Bax来保护心脏。我们将检验假设并描述帕金抑制Bax的分子机制。根据该项目的过度假设，即Bax和Parkin相互拮抗，以使心肌细胞受益：Bax的结合，可能在其细胞死亡激活构象中，可以抑制parkin介导的帕克蛋白介导的线粒体distion剂量。相反，Bax-Parkin相互作用抑制了BAX，这可能是通过干扰其活跃会议的过渡，从而抑制了心肌细胞凋亡和坏死。这是一个MPI应用，汇集了Richard Kitsis（心肌细胞死亡）和Gerald Dorn（心脏线粒体）的专业知识。这项研究非常重要，因为它将刺激现场 考虑和研究单个线粒体过程（例如细胞死亡和线粒体）之间的联系。此外，这将导致对帕金保护心脏的主要机制的重新考虑。这项工作也具有很高的创新性，因为以前尚未考虑大多数概念和关系。通过这项研究，我们将更好地了解缺血/再灌注和侵入后重塑期间急性心脏损伤的发病机理。