Coordinated Repair and Regeneration of Defective Mitochondria

有缺陷的线粒体的协调修复和再生

基本信息

批准号：
9412208
负责人：
Cole M Haynes
金额：
$ 41.2万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9412208
关键词：
Age Aging Aging-Related Process Attenuated Autophagocytosis Binding Biogenesis Cell Nucleus Cell division Cells Chronic Chronic stress Complex Consensus Sequence Data Defect Development Disease Environment Equilibrium Functional disorder Genes Genetic Transcription Genome Glycolysis Glycolysis Pathway Inherited Laboratories Longevity Mediating Metabolism Mitochondria Mitochondrial DNA Mitochondrial Proteins Molecular Chaperones Mutation Natural regeneration Normal Cell Nuclear Organelles Output Parkinson Disease Pathway interactions Peptide Hydrolases Play Proteins Recovery Regulation Repression Respiratory Chain Role Signal Pathway Stress Symptoms Time aged biological adaptation to stress common cellular transcription factor ATF insight mitochondrial dysfunction mutant normal aging novel novel therapeutics prevent programs promoter protein activation protein folding proteostasis public health relevance repaired respiratory response transcription factor

项目摘要

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.

描述（由申请人提供）：随着时间的推移，线粒体和呼吸链功能会下降，可能会导致衰老过程以及许多与年龄相关的疾病的发生。许多因素都有影响，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物本身的退化。一个突出的假设是，通过简单地诱导细胞增加线粒体生物合成，许多细胞缺陷和疾病症状都可以得到缓解。在本提案中，我们的目标是了解细胞在与年龄相关的线粒体功能障碍期间适应新陈代谢以及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）受到转录因子 ATFS-1 的调节，在线粒体应激过程中，ATFS-1 会导致保护性基因的转录诱导，包括线粒体伴侣和蛋白酶、抗 ROS 机制、线粒体裂变和自噬机制。最近，我们发现除了适应线粒体蛋白质稳态外，UPRmt 在适应代谢以促进“应激”线粒体内的呼吸链生物合成，同时诱导糖酵解途径以维持 ATP 水平方面也发挥着重要作用。在本提案中，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。我们已经鉴定出一种单独的转录因子 ZIP-3，它在线粒体应激过程中同时被激活，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 来微调呼吸链转录，以匹配应激细胞器中的蛋白质折叠能力并促进复杂的组装。我们预计，对这两条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发生的策略；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。目标 1 是确定 ATFS-1 如何调整呼吸链转录以促进应激期间的复杂组装。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。目标 2 是了解最近发现的转录因子 ZIP-3 在线粒体应激过程中如何受到调节以诱导呼吸链基因转录。目标 3 是了解这两种途径在正常衰老以及与年龄相关的压力期间如何整合，以促进呼吸链生物发生并影响寿命。