Coordinating mitochondrial network expansion and longevity via the Integrated Stress Response (ISR)

通过综合应激反应 (ISR) 协调线粒体网络扩张和寿命

基本信息

批准号：
10589511
负责人：
Cole M Haynes
金额：
$ 33.5万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10589511
关键词：
Address Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease patient Amino Acids Animals Biogenesis Biomass Caenorhabditis elegans Cell Culture Techniques Cell Line Cell Nucleus Cells Coupled Development Disease Endoplasmic Reticulum Genetic Transcription Growth Health Impairment Knock-out Longevity Mammalian Cell Mammals Mediating Messenger RNA Metabolic stress Mitochondria Mitochondrial Proteins Mutate Natural regeneration Nuclear Open Reading Frames Organism Orthologous Gene Output Parkinson Disease Pathology Pathway interactions Peptide Initiation Factors Phosphorylation Phosphotransferases Physiological Property Protein Biosynthesis Protein Import Protein Kinase Publishing Regulation Role Signal Pathway Stress System Testing Tissues Translations Untranslated Regions Work activating transcription factor 1 activating transcription factor 4 attenuation biological adaptation to stress cell age cell growth cell type common cellular transcription factor ATF healthy aging improved loss of function mutation mitochondrial dysfunction mutant normal aging oxidative damage programs trafficking transcription factor

项目摘要

Project Summary Mitochondrial function declines during normal aging and is accelerated in age-associated diseases such as Parkinson’s and Alzheimer’s. Thus, understanding how cells and organisms regulate mitochondrial network expansion during growth to meet cell-specific requirements, and maintain that mitochondrial network during aging, are essential steps to limiting pathologies associated with mitochondrial dysfunction and prolonging lifespan. Our published findings indicate that the mitochondrial network expansion that occurs during development is an emergent property of the synthesis of highly expressed mitochondrial proteins and ATFS-1- dependent mitochondrial UPR activation. Increased import flux of highly expressed mitochondrial proteins excludes the transcription factor ATFS-1 from mitochondria resulting in nuclear trafficking and UPRmt activation, which includes a mitochondrial biogenesis program. These findings suggest an interplay between protein synthesis, mitochondrial protein import capacity, and mitochondrial network expansion. Here, we examine the role of a translation control pathway known as the Integrated Stress Response (ISR) on the regulation of mitochondrial network expansion during development and aging. Surprisingly, our preliminary findings indicate that worms with an impaired ISR have substantially more mitochondrial biomass and increased longevity, suggesting potential approaches to recover mitochondrial function in aged cells. We hypothesize that the ISR provides two functions during cell growth; 1) it regulates protein synthesis rates via eIF2α phosphorylation so as not to overwhelm network assembly and expansion, and 2) increases ATFS-1/ATF5 expression to activate a transcriptional program to facilitate mitochondrial network expansion. While considerable work has demonstrated that the ISR is active during mitochondrial dysfunction, the functional outputs of the ISR as related to the mitochondrial network remain unclear. We will test this hypothesis in both C. elegans and mammalian cell culture via the following aims: 1. The role of the ISR in regulating mitochondrial network expansion in C. elegans. 2. Determine the impact of ISR-mediated translation regulation on C. elegans longevity. 3. Elucidate the role of the ISR in establishing a functional mitochondrial network in mammalian cells.

项目概要线粒体功能在正常衰老过程中会下降，而在与年龄相关的疾病中会加速，例如因此，了解细胞和生物体如何调节线粒体网络。生长过程中的扩张以满足细胞特定的需求，并在生长过程中维持线粒体网络衰老是限制与线粒体功能障碍相关的病理并延长寿命的重要步骤我们发表的研究结果表明，线粒体网络在生命周期中发生扩张。发育是高表达线粒体蛋白和 ATFS-1- 合成的一个新兴特性依赖线粒体 UPR 激活增加高表达线粒体蛋白的输入通量。将转录因子 ATFS-1 从线粒体中排除，导致核运输和 UPRmt 激活，其中包括线粒体生物发生程序这些发现表明蛋白质之间存在相互作用。合成、线粒体蛋白质输入能力和线粒体网络扩张。在这里，我们研究了称为综合应激反应的翻译控制途径的作用（ISR）对发育和衰老过程中线粒体网络扩张的调节。初步研究结果表明，ISR 受损的线虫具有更多的线粒体生物量并延长寿命，这表明恢复衰老细胞线粒体功能的潜在方法。 1）它通过调节蛋白质合成速率 eIF2α 磷酸化，以免压倒网络组装和扩展，2) 增加 ATFS-1/ATF5 表达激活转录程序以促进线粒体网络扩张。研究表明，ISR 在线粒体功能障碍期间处于活跃状态，ISR 的功能输出与线粒体网络的相关性仍不清楚。我们将在秀丽隐杆线虫和线虫中测试这一假设。哺乳动物细胞培养通过以下目标： 1. ISR 在调节线虫线粒体网络扩张中的作用。 2. 确定 ISR 介导的翻译调控对线虫寿命的影响。 3. 阐明ISR在哺乳动物细胞中建立功能性线粒体网络中的作用。