Maintenance of Mitochondrial Protein Folding as an Aging Effector

维持线粒体蛋白折叠作为衰老效应器

基本信息

批准号：
8332298
负责人：
Cole M Haynes
金额：
$ 37.49万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8332298
关键词：
5&apos Untranslated Regions Address Age Age of Onset Aging Aging-Related Process Animals Attenuated Binding Biogenesis Caenorhabditis elegans Caloric Restriction Cell Nucleus Cells Chaperone Gene Complex DNA biosynthesis Development Disease Electron Transport Environment Event Friedreich Ataxia Genetic Transcription Homeostasis Inner mitochondrial membrane Life Longevity Maintenance Malignant Neoplasms Mediating Metabolic Mitochondria Mitochondrial Matrix Mitochondrial Proteins Molecular Molecular Chaperones Mutation Nutrient Organelles Output Parkinson Disease Pathway interactions Peptide Hydrolases Peptide Initiation Factors Peptides Phosphorylation Phosphotransferases Physiological Proteins Pump Quality Control Reactive Oxygen Species Regulation Resistance Role Signal Pathway Signal Transduction Stress Stress Response Signaling Time Transcript Translating Translations attenuation biological adaptation to stress deprivation gain of function mitochondrial dysfunction mitochondrial genome mutant protein folding protein function research study response therapeutic development trafficking transcription factor

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial function and protein homeostasis are key contributors to the aging process and the onset of age- associated diseases. This proposal describes plans to examine mitochondrial protein folding and function in the context of C. elegans development and aging to further elucidate the molecular mechanisms cells employ to protect organelle function. Mitochondria are dynamic organelles, which are remodeled during diverse conditions including nutrient deprivation and cellular differentiation. Mitochondrial metabolic output has long been appreciated as a contributor to the aging process, primarily through the detrimental effects of reactive oxygen species generated by the electron transport chain. Additionally, mutations in the mitochondrial genome accumulate over time due to errors introduced during DNA replication. Both forms of damage challenge the already complex protein-folding environment in the organelle. To function properly during organelle remodeling and stress, the mitochondrial protein-folding environment must be maintained by molecular chaperones and proteases. We have identified a mitochondrial unfolded protein response, a signaling pathway that adjusts the organelle's folding capacity to the load of unfolded proteins that accumulate during stress by regulating the expression of mitochondrial chaperone genes. And, more recently we have discovered a requirement for a complementary translation regulation pathway. Consistent with a role in organelle protection, animals lacking components of either pathway are sensitive to conditions that perturb mitochondrial function. Here, we describe plans to further elucidate the mechanism of signal transduction within each pathway as well as their impact on development, aging and age-associated damage. Additionally, we plan to uncouple activation of each stress response pathway from mitochondrial biogenesis or stress to expand organelle folding capacity and determine the impact on lifespan and resistance to proteotoxicity.

描述（由申请人提供）：线粒体功能和蛋白质稳态是导致衰老过程和年龄相关疾病发作的关键因素。该提案描述了在秀丽隐杆线虫发育和衰老的背景下检查线粒体蛋白折叠和功能的计划，以进一步阐明细胞为保护细胞器功能所采用的分子机制。线粒体是动态细胞器，在不同的条件下进行了重塑，包括营养剥夺和细胞分化。长期以来，线粒体代谢输出一直被认为是衰老过程的贡献者，主要是通过电子传输链产生的活性氧的有害作用。另外，由于DNA复制过程中引入的误差，线粒体基因组中的突变会随着时间的推移而积累。两种形式的损害都挑战了细胞器中已经复杂的蛋白质折叠环境。为了在细胞器重塑和应力期间正常运行，必须通过分子伴侣和蛋白酶来维持线粒体蛋白质折叠环境。我们已经确定了线粒体展开的蛋白质反应，这是一种信号传导途径，该途径通过调节线粒体伴侣基因的表达来调节在应激过程中积累的有机蛋白的折叠能力。而且，最近我们发现了互补翻译调节途径的要求。与在细胞器保护中的作用一致，缺乏两种途径成分的动物对扰动线粒体功能的条件敏感。在这里，我们描述了进一步阐明每种途径内信号转导机理的计划，以及它们对发展，衰老和年龄相关损害的影响。此外，我们计划从线粒体生物发生或应力中取消激活每个应力响应途径，以扩大细胞器折叠能力，并确定对寿命和对蛋白质毒性的抗性的影响。