Autophagy and Megamitochondria in Cardiac Aging and Heart Failure

心脏衰老和心力衰竭中的自噬和巨线粒体

• 批准号: 10592312
• 负责人: Asa B. Gustafsson
• 金额: $ 48.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592312
• 关键词: Acceleration; Age; Aging; Autophagocytosis; Autophagosome; BCL2 gene; Biochemical; Cardiac; Cardiac Myocytes; Cardiac health; Cardiovascular Diseases; Cardiovascular system; Cell Aging; Cell Death Induction; Cells; Co-Immunoprecipitations; Complex; Contracts; Data; Degradation Pathway; Development; Disease; Fibrosis; Generations; Goals; Heart; Heart Diseases; Heart failure; Homeostasis; Hypertrophy; Incidence; Intervention; Life Expectancy; Link; Lysosomes; Mediating; Mitochondria; Mitochondrial DNA; Molecular; Morphology; Mus; Muscle Cells; Organelles; Oxidative Stress; Pathology; Pathway interactions; Predisposition; Prevalence; Process; Production; Proteins; Reactive Oxygen Species; Research; Respiration; Role; Stress; Testing; Time; Tissues; Transgenic Mice; Western Blotting; age related; aged; cardiovascular risk factor; catalase; experimental study; heart function; insight; middle age; mitochondrial dysfunction; mitochondrial permeability transition pore; myocardial damage; new therapeutic target; older patient; overexpression; preservation; prevent; programs; protein aggregation

Project summary As average life expectancy continues to rise in the developed world, age associated pathologies are increasingly prevalent. Aging is a major risk factor for cardiovascular diseases and the hallmarks of cardiac aging include loss of myocytes, fibrosis and hypertrophy, all of which contribute to increased incidence of cardiac disease. At the molecular level, cellular aging is characterized by increased reactive oxygen species (ROS) production, mitochondrial dysfunction and accumulation of damaged proteins and organelles. Cardiac myocytes rely upon autophagy, a lysosome-mediated degradation pathway, to remove toxic protein aggregates and damaged organelles from the cellular milieu. Increasing lines of evidence point to an age- associated decrease in myocyte autophagy, with predictably negative consequences for cardiac function and health. However, it is still unclear why autophagy declines with age and whether specific proteins or pathways involved in regulating autophagy are altered with age. Mitochondrial dysfunction is also a key hallmark of aging and has been linked to a number of age-related pathologies, including heart failure. In addition, enlarged or megamitochondria are often present in aged tissues, but their potential contribution to the aging process and disease development remain unknown. We have confirmed that autophagic activity is reduced in aged mouse hearts which correlates with accumulation of ubiquitinated mitochondria. Our preliminary data also suggest that the decrease in autophagic activity in the aged heart is due to altered expression of Atg9b, a key regulator of autophagosome formation and elongation. We also found that the aged mouse heart contains a substantial number of enlarged mitochondria. Why these megamitochondria form with age in the heart and whether they contribute to the aging process are currently unknown. In this proposal, we will examine the hypothesis that a decline in autophagosome formation and mitochondrial clearance in the aging heart leads to increased fusion between dysfunctional and healthy mitochondria in an attempt to dilute damaged components. Over time, these megamitochondria accumulate increased levels of damage. They become less functional and generate increased ROS, which directly contribute to the cardiac aging process. This hypothesis will be tested with two specific aims. Specific aim 1 will dissect the mechanism underlying the age-associated decline in autophagy. Specific aim 2 will characterize the interplay between mitochondrial morphology and autophagy during aging. We will also investigate if restoring Atg9b will enhance baseline autophagy in the aged hearts and whether reduced mitochondrial ROS production will prevent or delay the age associated decline in autophagy and abrogate formation of harmful megamitochondria. Overall, these studies will further our understanding of the molecular mechanism underlying the aging process and help identify interventions to preserve mitochondrial homeostasis and prevent development of disease.

项目摘要 随着发达国家的平均预期寿命持续上升，与年龄相关的病理是 越来越普遍。衰老是心血管疾病的主要危险因素和心脏的标志 衰老包括肌细胞的丧失，纤维化和肥大，所有这些都导致出现率增加 心脏病。在分子水平上，细胞衰老的特征是活性氧增加 （ROS）生产，线粒体功能障碍以及受损蛋白质和细胞器的积累。心脏 肌细胞依赖于溶酶体介导的降解途径自噬去除有毒蛋白 细胞环境中的聚集体和受损细胞器。越来越多的证据表明年龄 肌细胞自噬的相关减少，对心脏功能和 健康。但是，目前尚不清楚为什么自噬随着年龄的年龄而下降以及特定蛋白质或途径 随着年龄的增长，参与调节自噬的情况会改变。线粒体功能障碍也是衰老的关键标志 并与许多与年龄有关的病理（包括心力衰竭）有联系。另外，放大或 巨蛋白软糖通常在老化的组织中存在，但它们对衰老过程的潜在贡献和 疾病发展仍然未知。我们已经确认在老年小鼠中降低了自噬活动 与泛素化线粒体的积累相关的心脏。我们的初步数据也表明 老年心脏自噬活动的降低是由于ATG9B表达的改变，ATG9B是一个关键的调节剂 自噬体形成和伸长。我们还发现，老年小鼠心脏包含大量 线粒体扩大数量。为什么这些巨蛋白软糖会随着内心的年龄以及是否形成 目前尚不清楚为老化过程做出贡献。在该提议中，我们将研究以下假设 衰老心脏中自噬体形成和线粒体清除的下降导致融合增加 在功能障碍和健康的线粒体之间，试图稀释受损的组件。随着时间的推移， 这些巨头集团会积累增加的损害水平。它们的功能降低并产生 ROS增加，这直接导致心脏老化过程。该假设将通过两个检验 具体目标。具体目标1将剖析自噬相关下降的基础机制。 特定的目标2将表征衰老过程中线粒体形态与自噬之间的相互作用。 我们还将调查恢复ATG9B是否会增强老年人心中的基线自噬，以及是否是否会增强其 线粒体ROS的产生降低将预防或延迟自噬的年龄下降和 废除有害的巨蛋白结合体的形成。总体而言，这些研究将进一步我们对 衰老过程的基本分子机制并有助于确定干预措施以保留线粒体 稳态并防止疾病的发展。