Modulation of mitochondrial biogenesis by the Integrated Stress Response (ISR)

通过综合应激反应 (ISR) 调节线粒体生物合成

• 批准号: 10657862
• 负责人: Sookyung Kim
• 金额: $ 0.25万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-05 至 2027-05-04
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657862
• 关键词: Age; Aging; Alzheimer' s Disease; Amino Acids; Animals; Biogenesis; Biology; Caenorhabditis elegans; Cell Nucleus; Cell physiology; Cells; Development; Disease; Disease Progression; Ensure; Equipment; Exhibits; Functional disorder; Genetic; Genetic Transcription; Growth Factor; Health; Impairment; Individual; Link; Longevity; Mediating; Metabolic; Mitochondria; Mitochondrial Proteins; Muscle; Muscle function; Mutation; Neurodegenerative Disorders; Neurons; Output; PERK kinase; Parkinson Disease; Pathway interactions; Peptide Initiation Factors; Phosphorylation Site; Phosphotransferases; Physiological; Play; Property; Protein Biosynthesis; Protein Import; Proteins; Reagent; Recovery; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stress; Testing; Therapeutic; Translations; Work; activating transcription factor 1; activating transcription factor 4; aged; attenuation; biological adaptation to stress; cell growth; cell type; common cellular transcription factor ATF; deprivation; endoplasmic reticulum stress; healthspan; healthy aging; improved; mitochondrial dysfunction; mitochondrial genome; mutant; novel; overexpression; prevent; programs; response; stressor; therapy development; transcription factor

Project Summary Mitochondrial function declines during aging. The dysfunction is accelerated in age-associated diseases such as Alzheimer’s Disease and Parkinson’s Disease. Thus, therapeutic approaches to maintain or recover mitochondrial function may promote healthy aging or slow age-associated disease progression. Recently, we have shown that the mitochondrial network expansion that occurs during development is an emergent property of the synthesis of highly expressed mitochondrial proteins. Increased mitochondrial import of the highly expressed mitochondrial proteins outcompete the transcription factor ATFS-1, preventing it from entering mitochondria. This allows ATFS-1 to traffic to the nucleus and activate a mitochondrial network expansion transcription program known as UPRmt. These findings suggest an interplay between protein synthesis, mitochondria protein import capacity, and mitochondrial network expansion. The Integrated Stress Response (ISR) is a translation control pathway that reduces overall protein synthesis while preferentially increases translation of ATF-4 in response to diverse stressors including amino acid depletion, ER dysfunction and mitochondrial perturbations. The ISR is mediated by 4 kinases (3 in C. elegans) that all phosphorylate the translation initiation factor eIF2α, which in turn modulates protein synthesis. While considerable work has demonstrated that the ISR is active in response to mitochondrial perturbation, the functional outputs of the ISR related to mitochondrial biology remain unknown. I have obtained or generated several C. elegans strains in which the ISR is impaired. Quite surprisingly, these worms have increased mitochondrial mass and mitochondrial genomes. Intriguingly, these animals also live significantly longer than wildtype worms, suggesting that increased mitochondrial mass is sufficient to extend organismal lifespan. I hypothesize that the ISR matches mitochondrial network expansion with the physiological and environmental inputs that activate the ISR by antagonizing ATFS-1 function. Here, I focus on the role of ISR-dependent translation attenuation or ATF-4 synthesis as direct or indirect regulators of ATFS-1-dependent transcription via the following aims. 1. Determine the mechanisms by which the ISR regulates ATFS-1-dependent mitochondrial biogenesis. 2. Elucidate the mechanisms by which the ISR modulates longevity and healthspan.

项目摘要 线粒体功能在衰老过程中会下降。功能障碍在与年龄相关的疾病中加速，如 如阿尔茨海默氏症和帕金森氏症。因此，维持或恢复的治疗方法 线粒体功能可能促进健康衰老或减缓与年龄相关的疾病进展。最近，我们 已经表明，在发育过程中发生的线粒体网络扩张是一种紧急性质 高表达线粒体蛋白的合成。高度的线粒体进口增加 表达的线粒体蛋白与转录因子ATFS-1竞争，阻止其进入 线粒体。这使得ATFS-1能够向细胞核进行交通，并激活线粒体网络的扩展 转录程序称为UPRmt。这些发现表明蛋白质合成和蛋白质合成之间存在相互作用 线粒体蛋白质输入能力，以及线粒体网络扩张。 整合应激反应(ISR)是一种降低蛋白质总量的翻译控制途径 合成，同时优先增加ATF-4的翻译以响应包括氨基酸在内的不同应激源 酸耗竭、内质网功能障碍和线粒体紊乱。ISR由4种激酶介导(C. 都能使翻译起始因子eIF2α磷酸化，进而调节蛋白质合成。 虽然大量研究表明ISR对线粒体扰动的反应是活跃的，但 ISR与线粒体生物学相关的功能输出仍不清楚。我已经获得或生成了 几种ISR受损的线虫菌株。令人惊讶的是，这些蠕虫增加了 线粒体质量和线粒体基因组。有趣的是，这些动物的寿命也明显长于 野生型蠕虫，这表明增加的线粒体质量足以延长有机体的寿命。我 假设ISR将线粒体网络的扩张与生理和环境相匹配 通过拮抗ATFS-1功能来激活ISR的输入。在这里，我将重点介绍依赖ISR的角色 翻译衰减或ATF-4合成作为ATFS-1依赖转录的直接或间接调节因子 目标有以下几点。 1.确定ISR调控ATFS-1依赖的线粒体生物发生的机制。 2.阐明ISR调节长寿和健康的机制。