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: 10640101
• 负责人: Sookyung Kim
• 金额: $ 3.5万
• 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/10640101
• 关键词: Acceleration; Age; Aging; Alzheimer' s Disease; Amino Acids; Animals; Biogenesis; Biology; Caenorhabditis elegans; Cell Nucleus; Cell physiology; Cells; Development; Disease; Disease Progression; EIF-2alpha; 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; 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; human old age (65+); 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下降。这种功能障碍在与年龄相关的疾病中会加速， 老年痴呆症和帕金森症因此，维持或恢复的治疗方法 线粒体功能可以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新出现的特性， 高度表达的线粒体蛋白质的合成。增加线粒体输入的高度 表达的线粒体蛋白质竞争超过转录因子ATFS-1，阻止其进入 线粒体这使得ATFS-1能够运输到细胞核并激活线粒体网络扩展 转录程序称为UPRmt。这些发现表明蛋白质合成， 线粒体蛋白质输入能力和线粒体网络扩展。 整合应激反应（ISR）是一种翻译控制途径， 合成，同时优先增加ATF-4的翻译，以响应不同的应激源，包括氨基 酸消耗、ER功能障碍和线粒体扰动。ISR由4种激酶介导（C. elegans），都磷酸化翻译起始因子eIF 2 α，这反过来又调节蛋白质合成。 虽然大量的工作已经证明ISR在响应线粒体扰动时是活跃的，但是， 与线粒体生物学相关的ISR的功能输出仍然未知。我已经获得或生成了 几个C。elegans菌株，其中ISR受损。令人惊讶的是，这些蠕虫的数量有所增加 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，这表明增加线粒体质量足以延长生物体寿命。我 假设ISR将线粒体网络扩展与生理和环境相匹配， 通过拮抗ATFS-1功能激活ISR的输入。在这里，我重点介绍ISR依赖的作用 作为ATFS-1依赖性转录的直接或间接调节剂， 以下目标。 1.确定ISR调节ATFS-1依赖的线粒体生物合成的机制。 2.阐明ISR调节寿命和健康寿命的机制。