Mitochondrial Quality Control in the Aging Myocardium

衰老心肌中的线粒体质量控制

• 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
• 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

 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(由申请人提供)：心血管疾病仍然是老年人的重大健康风险，老龄化本身显著增加了心血管疾病的发病率。因此，更好地了解衰老的病理生理机制是至关重要的。功能障碍的线粒体在细胞中的积累被认为是衰老过程和许多与年龄相关的病理的原因之一，但为什么这些线粒体在衰老的细胞中积累目前尚不清楚。在心脏中，线粒体的主要功能是满足 通过氧化磷酸化提供三磷酸腺苷对跳动的心肌细胞的高能量需求。然而，线粒体可以迅速转变为促进死亡的细胞器。它们可以过度产生活性氧物种，并释放致死蛋白。不足为奇的是，细胞已经形成了一种防御机制，以抵御可能对细胞造成伤害的异常线粒体。研究发现，功能失调的线粒体会被自噬小体迅速隔离，然后被运送到溶酶体进行降解。最近的研究表明，E3泛素连接酶Parkin在标记细胞中功能障碍的线粒体降解方面发挥着重要作用。Parkin泛素化外膜中的蛋白质，作为自噬小体吞噬它们的标签。尽管已有研究报道Parkin在适应急性应激中起着重要作用，但到目前为止还没有研究集中于Parkin在心肌细胞老化中的作用。在这个探索性的提案中，我们将调查Parkin介导的有丝分裂吞噬在预防年龄相关性心肌病发展中发挥重要作用的假设。不幸的是，线粒体清除率随着年龄的增长而降低，这导致功能障碍的线粒体积累。我们推测，老年心肌线粒体清除减少是由Parkin的氧化修饰和失活引起的。这些假说将通过两个目标进行检验。目的1探讨Parkin介导的线粒体清除在预防老年性心肌病中的重要性。使用携带有缺陷线粒体DNA聚合酶γPOLGm/m的小鼠模型，我们将在体外和体内研究Parkin在清除线粒体积累的线粒体突变方面的重要性。我们还将POLGm/m小鼠与Parkin缺陷小鼠和心脏特异性Parkin转基因小鼠杂交，以探讨其对线粒体清除和年龄相关性心肌病的影响。在目标2中，我们将研究老化心肌中氧化应激增加是否导致Parkin错误折叠和失活。这些研究将为Parkin介导的有丝分裂吞噬在预防年龄相关性心肌病中的作用提供重要的新见解。