Mitochondrial Quality Control in the Aging Myocardium

衰老心肌中的线粒体质量控制

基本信息

批准号：
9265769
负责人：
Asa B. Gustafsson
金额：
$ 19.38万
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：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9265769
关键词：
Affect Age Aging Aging-Related Process Apoptosis Autophagosome Cardiac Cardiomyopathies Cardiovascular Diseases Cardiovascular system Cell Aging Cells Cessation of life Contracts Cysteine DNA DNA-Directed DNA Polymerase Defect Defense Mechanisms Development Diabetes Mellitus Disease Elderly Fibrosis Goals Health Heart Homeostasis Hypertension Impairment In Vitro Investigation Label Lead Lysosomes Mediating Membrane Mitochondria Mitochondrial DNA Modification Molecular Monitor Morbidity - disease rate Mus Muscle Cells Mutation Myocardium Organelles Oxidative Phosphorylation Oxidative Stress Pathology Pathway interactions Phenotype Play Premature aging syndrome Process Proteins Quality Control Reactive Oxygen Species Reporting Research Risk Risk Factors Role Solubility Testing Transgenic Mice Ubiquitination acute stress age related aged epidemiology study in vivo insight mitochondrial DNA mutation mitochondrial autophagy mouse model new therapeutic target novel parkin gene/protein prevent programs public health relevance response ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular disease remains a significant health risk for the elderly and aging itself significantly increases cardiovascular morbidity. Therefore, better understanding of the pathophysiological mechanisms underlying aging is critical. Accumulation of dysfunctional mitochondria in cells has been implicated as a cause of the aging process and a number of age-related pathologies but why these mitochondria accumulate in aging cells is currently unclear. In the heart, the primary function of mitochondria is to meet the high energy demand of the beating myocytes by providing ATP through oxidative phosphorylation. However, mitochondria can quickly change into death-promoting organelles. They can become excessive producers of reactive oxygen species and release pro-death proteins. Not surprisingly, cells have developed a defense mechanism against aberrant mitochondria that can cause harm to the cell. Studies have found that dysfunctional mitochondria are rapidly sequestered by autophagosomes and subsequently delivered to lysosomes for degradation. Recent studies have demonstrated that the E3 ubiquitin ligase Parkin plays an important role in marking dysfunctional mitochondria for degradation in cells. Parkin ubiquitinates proteins in the outer membrane which serves as labels for the autophagosomes to engulf them. Although studies have reported that Parkin plays an important role in adapting to acute stress, no studies to date have focused on Parkin's role in aging myocytes. In this exploratory proposal, we will investigate the hypothesis that Parkin-mediated mitophagy plays an important role in preventing development of age-related cardiomyopathy. Unfortunately, mitochondrial clearance is decreased with age which leads to accumulation of dysfunctional mitochondria. We hypothesize that the reduced mitochondrial clearance in the aged myocardium is caused by oxidative modification and inactivation of Parkin. These hypotheses will be tested with two aims. Aim 1 will explore the importance of Parkin-mediated mitochondrial clearance in preventing age-related cardiomyopathy. Using a mouse model carrying a proofreading defective mitochondrial DNA polymerase γPOLGm/m), we will investigate the importance of Parkin in clearing mitochondria with accumulating mtDNA mutations in vitro and in vivo. We have also crossed the POLGm/m mice with Parkin deficient mice and cardiac specific Parkin transgenic mice to explore the effect on mitochondrial clearance and age-related cardiomyopathy. In aim 2, we will investigate whether increased oxidative stress in the aging myocardium contributes to misfolding and inactivation of Parkin. These studies will provide important novel insight into the role of Parkin-mediated mitophagy in preventing age-related cardiomyopathy.

描述（由适用提供）：心血管疾病仍然是老年人和衰老本身的重大健康风险，可显着增加心血管发病率。因此，更好地了解衰老的病理生理机制至关重要。细胞中线粒体功能失调的积累已被实施是衰老过程和许多与年龄有关的病理学的原因，但是为什么目前尚不清楚这些线粒体丙烯酸的原因。在心中，线粒体的主要功能是满足通过氧化物磷酸化提供ATP，对跳动肌细胞的高能量需求。但是，线粒体可以迅速变成促进死亡的细胞器。它们可以成为活性氧的过量生产者，并释放pro死亡蛋白。毫不奇怪，细胞已经开发出一种防御机制，以抗异常的线粒体，这可能会对细胞造成伤害。研究发现，功能障碍的线粒体被自噬体迅速隔离，随后递送到溶酶体降解。最近的研究表明，E3泛素连接酶Parkin在标记功能障碍的线粒体降解中起着重要作用。 Parkin泛素蛋白质中的蛋白质是外膜的蛋白质，该蛋白是吞噬它们的自噬体的标签。尽管研究报告说，帕金在适应急性压力方面起着重要作用，但迄今为止，迄今为止，还没有研究帕金在衰老肌细胞中的作用。在这项探索性建议中，我们将研究以下假设：帕金介导的线粒体在防止与年龄相关的心肌病的发展中起着重要作用。不幸的是，线粒体清除随着年龄的增长而降低，从而导致线粒体功能失调。我们假设老年心肌中的线粒体清除率降低是由帕金蛋白的氧化修饰和失活引起的。这些假设将以两个目标进行检验。 AIM 1将探讨帕金介导的线粒体清除在预防与年龄相关的心肌病中的重要性。使用带有校对有缺陷的线粒体DNA聚合酶γpolgm/m的小鼠模型，我们将研究帕克蛋白在清除线粒体的重要性，并在体外和体内积聚mtDNA突变。我们还与帕金蛋白不足的小鼠和心脏特异性帕克蛋白转基因小鼠跨越了POLGM/M小鼠，以探索对线粒体清除和与年龄相关的心肌病的影响。在AIM 2中，我们将调查衰老心肌中增加的氧化应激是否有助于帕金的错误折叠和失活。这些研究将为帕金介导的线粒体在预防与年龄相关的心肌病中的作用提供重要的新见解。