Maintenance of Mitochondrial Protein Folding as an Aging Effector

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病的关键因素。这项建议描述了在线虫发育和衰老的背景下研究线粒体蛋白质折叠和功能的计划，以进一步阐明细胞用来保护细胞器功能的分子机制。线粒体是动态细胞器，在包括营养剥夺和细胞分化在内的各种条件下都会重塑。长期以来，线粒体代谢产物一直被认为是衰老过程的一个贡献者，主要是通过电子传递链产生的活性氧物种的有害影响。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本已复杂的蛋白质折叠环境构成了挑战。为了在细胞器重塑和应激期间正常发挥作用，线粒体蛋白质折叠环境必须由分子伴侣和蛋白酶来维持。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来调节细胞器的折叠能力，以适应应激期间积累的未折叠蛋白的负载。而且，最近我们发现需要一个互补的翻译调控途径。与细胞器保护作用一致的是，缺乏这两种途径中的任何一种成分的动物对扰乱线粒体功能的条件都很敏感。在这里，我们描述了进一步阐明每条通路中的信号转导机制以及它们对发育、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从线粒体生物发生或应激中分离出来，以扩大细胞器的折叠能力，并确定对寿命和对蛋白毒性的抵抗力的影响。 公共卫生相关性：线粒体功能障碍在从帕金森氏症和弗里德里希共济失调到癌症的各种疾病中普遍存在。细胞会对线粒体的侮辱做出反应，但应激反应最终会被压倒，导致疾病状态。彻底了解细胞用来保护线粒体功能障碍的分子通路将有助于开发潜在能够限制年龄或与疾病相关的线粒体损伤的治疗操作。

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. PUBLIC HEALTH RELEVANCE: Mitochondrial dysfunction is prevalent in diseases ranging from Parkinson's and Friedreich's ataxia to cancer. Cells respond to mitochondrial insults but the stress responses are eventually overwhelmed leading to the disease state. A thorough understanding of the molecular pathways cells employ to protect against mitochondrial dysfunction will allow for the development of therapeutic manipulations potentially able to limit age or disease-associated mitochondrial damage.