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。该提案描述了在秀丽隐杆线虫发育和衰老的背景下研究线粒体蛋白折叠和功能的计划，以进一步阐明细胞用于保护细胞器功能的分子机制。线粒体是一种动态细胞器，在营养剥夺和细胞分化等多种条件下进行重构。线粒体代谢输出长期以来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随着时间的推移而积累。这两种形式的损伤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激过程中正常发挥作用，线粒体蛋白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来调节细胞器的折叠能力，以适应应激过程中积累的未折叠蛋白的负荷。最近，我们发现了对互补翻译调控途径的需求。与在细胞器保护中的作用一致，缺乏任何途径成分的动物对扰乱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，我们计划从线粒体生物发生或应激中解耦激活每个应激反应途径，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。

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.