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衰老过程和年龄相关疾病发生的关键因素。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质折叠和功能的计划，以进一步阐明细胞用于保护细胞器功能的分子机制。线粒体是动态细胞器，会在营养缺乏和细胞分化等多种条件下进行重塑。长期以来，线粒体代谢输出一直被认为是衰老过程的一个促成因素，主要是通过电子传递链产生的活性氧的有害影响。此外，由于 DNA 复制过程中引入的错误，线粒体基因组中的突变会随着时间的推移而积累。这两种形式的损伤都对细胞器中已经很复杂的蛋白质折叠环境提出了挑战。为了在细胞器重塑和应激过程中正常发挥作用，线粒体蛋白质折叠环境必须由分子伴侣和蛋白酶维持。我们已经确定了线粒体未折叠蛋白反应，这是一种信号通路，通过调节线粒体伴侣基因的表达，调整细胞器的折叠能力以适应应激期间积累的未折叠蛋白的负载。而且，最近我们发现需要互补的翻译调控途径。与细胞器保护中的作用一致，缺乏任一途径成分的动物对扰乱线粒体功能的条件很敏感。在这里，我们描述了进一步阐明每个通路内信号转导机制及其对发育、衰老和年龄相关损伤的影响的计划。此外，我们计划将每个应激反应途径的激活与线粒体生物发生或应激分开，以扩大细胞器折叠能力并确定对寿命和蛋白毒性抵抗力的影响。