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.

项目总结 随着发达国家平均预期寿命的持续增长，与年龄相关的疾病 变得越来越普遍。衰老是心血管疾病的主要危险因素，也是心脏病的标志 衰老包括心肌细胞的丧失、纤维化和肥大，所有这些都会增加糖尿病的发病率。 心脏病。在分子水平上，细胞衰老的特征是活性氧的增加。 (ROS)的产生、线粒体功能障碍以及受损蛋白质和细胞器的积累。心脏 肌细胞依靠自噬来清除有毒蛋白质，这是一种溶酶体介导的降解途径。 来自细胞环境的聚集和损坏的细胞器。越来越多的证据指向一个时代- 与心肌细胞自噬相关的减少，对心功能和 健康。然而，目前还不清楚自噬为什么会随着年龄的增长而下降，也不清楚是否有特定的蛋白质或途径。 参与调节自噬的基因随着年龄的增长而改变。线粒体功能障碍也是衰老的一个重要标志 并与许多与年龄相关的病理有关，包括心力衰竭。此外，放大或 巨线粒体通常存在于衰老的组织中，但它们对衰老过程和 疾病的发展仍然未知。我们已经证实，衰老小鼠的自噬活性降低 心脏，这与泛素化线粒体的积累有关。我们的初步数据还表明， 老年心脏自噬活性的降低是由于Atg9b的表达改变所致，Atg9b是心脏自噬的关键调节因子 自噬小体的形成和伸长。我们还发现，老化的小鼠心脏含有大量的 线粒体数增大。为什么这些巨型线粒体在心脏中随着年龄的增长而形成，以及它们是否 导致衰老过程的因素目前尚不清楚。在这个提案中，我们将检验一个假设 老化心脏自噬小体形成和线粒体清除能力下降导致融合增加 在功能失调的线粒体和健康的线粒体之间，试图稀释受损的成分。随着时间的推移, 这些巨型线粒体累积的损伤程度更高。它们的功能变得不那么强大，并产生 ROS增加，这直接导致心脏老化过程。这一假设将通过两个例子进行检验 明确的目标。具体目标1将剖析与年龄相关的自噬下降的机制。 具体目标2将描述衰老过程中线粒体形态和自噬之间的相互作用。 我们还将调查修复Atg9b是否会增强老年心脏的基线自噬能力，以及是否 线粒体ROS产生的减少将防止或延缓与年龄相关的自噬和 废除有害的巨型线粒体的形成。总体而言，这些研究将加深我们对 衰老过程的分子机制并有助于确定保护线粒体的干预措施 动态平衡和预防疾病的发展。