Coordinated Repair and Regeneration of Defective Mitochondria

描述（由申请人提供）：随着时间的推移，线粒体和呼吸链功能下降，可能导致衰老过程以及许多年龄相关疾病的发生。许多因素包括呼吸链基因中的线粒体和核基因组突变以及呼吸链复合体本身的变性。一个突出的假设是，通过简单地诱导细胞增加线粒体生物合成，可以减轻许多细胞缺陷和疾病症状。在这项提案中，我们的目标是了解细胞在年龄相关的线粒体功能障碍期间适应代谢以及促进呼吸链生物合成的内在途径。 我们已经证明，线粒体未折叠蛋白（UPRmt）是由转录因子ATFS-1，在线粒体应激导致转录诱导的保护基因，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的调节。最近，我们发现，除了适应线粒体蛋白质稳态，UPRmt也有一个突出的作用，在适应代谢，以促进呼吸链生物合成内的“应激”线粒体，同时诱导糖酵解途径，以维持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，这是同时激活线粒体应激，特异性诱导呼吸链基因的转录。有趣的是，我们的初步数据表明，ATFS-1通过拮抗ZIP-3微调呼吸链转录，以匹配应激细胞器中的蛋白质折叠能力并促进复合物组装。我们预计，对这两种途径之间相互作用的全面了解将揭示细胞在次优条件下增加线粒体生物合成的策略;这种情况可能与发育或正常细胞分裂期间发现的情况完全不同。 目的1是确定ATFS-1如何调节呼吸链转录，以促进复杂的组装过程中的压力。我们的初步数据表明，ATFS-1直接结合到两个基因组中的启动子的一种新的调节形式。 目的2是了解最近发现的转录因子ZIP-3在线粒体应激过程中是如何调控呼吸链基因转录的。 目的3是了解这两种途径如何在正常衰老以及与年龄相关的压力下整合，以促进呼吸链生物合成并影响寿命。

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.