Coordinated Repair and Regeneration of Defective Mitochondria

描述(由申请人提供)：线粒体和呼吸链功能随着时间的推移而下降，可能导致衰老过程以及许多与年龄相关的疾病的发生。原因很多，包括呼吸链基因的线粒体和核基因组突变，以及呼吸链复合体本身的退化。一个突出的假设是，通过简单地诱导细胞增加线粒体的生物生成，许多细胞缺陷和疾病症状可以得到缓解。在这项建议中，我们的目标是了解细胞在年龄相关线粒体功能障碍期间用来适应新陈代谢和促进呼吸链生物发生的内在途径。我们已经证明，线粒体未折叠蛋白(UPRmt)受转录因子ATFS-1的调控，在线粒体应激过程中，转录因子ATFS-1导致保护基因的转录诱导，包括线粒体伴侣和蛋白酶、抗ROS机制、线粒体分裂和自噬机制。最近，我们发现，除了适应线粒体蛋白平衡外，UPRmt还在适应代谢方面发挥着重要作用，以促进“应激”线粒体内呼吸链的生物发生，同时诱导糖酵解途径维持ATP水平。在这项提案中，我们的目标是了解UPRmt与最近发现的单独的线粒体保护性应激反应的相互作用。我们已经确定了一个单独的转录因子ZIP-3，它在线粒体应激时同时激活，特异性地诱导呼吸链基因的转录。目的1是确定ATFS-1如何在应激状态下调节呼吸链转录以促进复杂的组装。我们的初步数据表明了一种新的调控形式，其中ATFS-1直接与两个基因组中的启动子结合。目的2了解新近发现的转录因子ZIP-3在线粒体应激过程中如何调控呼吸链基因的转录。目的3是了解这两条途径如何在正常衰老和年龄相关的应激中整合，以促进呼吸链的生物发生和影响寿命。

DESCRIPTION (provided by applicant): A decline in mitochondrial and respiratory chain function occurs over time and likely contributes to the aging process as well as to the onset of numerous age-associated diseases. Many factors contribute including mitochondrial and nuclear genome mutations in respiratory chain genes as well as the degeneration of the respiratory chain complexes themselves. A prominent hypothesis is that by simply inducing cells to increase mitochondrial biogenesis, many of the cellular defects and disease symptoms can be alleviated. In this proposal, we aim to understand the intrinsic pathways employed by cells to adapt metabolism as well as promote respiratory chain biogenesis during age-associated mitochondrial dysfunction. We have demonstrated that the mitochondrial unfolded protein (UPRmt) is regulated by the transcription factor ATFS-1, which during mitochondrial stress leads to the transcriptional induction of protective genes including mitochondrial chaperones and proteases, anti-ROS machinery, mitochondrial fission and autophagy machinery. More recently, we have found that in addition to adapting mitochondrial proteostasis, the UPRmt also has a prominent role in adapting metabolism to promote respiratory chain biogenesis within "stressed" mitochondria while inducing the glycolysis pathway to maintain ATP levels. In this proposal, we aim to understand the interaction of the UPRmt with a separate, recently discovered, mitochondrial protective stress response. We have identified a separate transcription factor, ZIP-3, that is simultaneously activated during mitochondrial stress that specifically induces transcription of respiratory chain genes. Interestingly, our preliminary data suggest that ATFS-1 fine-tunes respiratory chain transcription by antagonizing ZIP-3, to match the protein-folding capacity in the stressed organelle and promote complex assembly. We anticipate a complete understanding of the interactions between these two pathways will reveal strategies cells employ to increase mitochondrial biogenesis during suboptimal conditions; a scenario potentially quite different than that found during development or normal cell division. Aim 1 is to determine how ATFS-1 adjusts respiratory chain transcription to promote complex assembly during stress. Our preliminary data suggest a novel form of regulation where ATFS-1 binds directly to promoters in both genomes. Aim 2 is to understand how the recently identified transcription factor ZIP-3 is regulated during mitochondrial stress to induce respiratory chain gene transcription. Aim 3 is to understand how these two pathways integrate during normal aging as well as age- associated stress to promote respiratory chain biogenesis and impact longevity.