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：
10560647
负责人：
Cole M Haynes
金额：
$ 44.65万
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 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10560647
关键词：
ATP-Dependent Proteases Acceleration Age Aging Alzheimer&apos s Disease Animals Binding Biogenesis Cell Nucleus Cells Constitution Constitutional Data Development Developmental Delay Disorders Diapause Disease Ensure Feedback Fibroblasts Functional disorder Funding Genes Genetic Transcription Health Heterogeneity Individual Insulin Receptor Link Longevity Mediating Mitochondria Mitochondrial DNA Mitochondrial Proteins Muscle Natural regeneration Neurons Nuclear Organelles Organism Parkinson Disease Pathology Peptide Hydrolases Physiological Physiology Polymerase Proteins Receptor Signaling Recovery Regulation Signal Pathway Specific qualifier value Stress Testing Time ZIP protein activating transcription factor 1 bZIP Protein cell growth cell type common cellular transcription factor ATF misfolded protein mitochondrial autophagy mitochondrial dysfunction mitochondrial genome programs repaired response sensor transcription factor

项目摘要

Project Summary Mitochondrial function declines during aging and is accelerated in age-associated diseases such as Parkinson's and Alzheimer's. Thus, understanding how cells and organisms generate the appropriate mitochondrial mass during development and maintain that mitochondrial network during aging is an essential step to limiting pathologies associated with loss of mitochondrial function. Here, we aim to understand the underlying mechanisms by which the transcription factor ATFS-1 and the mitochondrial unfolded protein response (UPRmt) coordinate mitochondrial network biogenesis during normal development and the recovery of the mitochondrial network via independently regulated functions of ATFS-1 in mitochondrial compartments and the nucleus. Numerous components have been identified that promote replication of the mitochondrial genome and transcription of nuclear-encoded genes that result in mitochondrial biogenesis. However, it remains unclear how the appropriate amount of mitochondrial mass is achieved during development or cell specification, and how the mitochondrial network is maintained over a cell or organisms lifetime. It also remains unknown if mitochondrial genome (mtDNA) replication is coordinated with cell growth, physiology, or functional heterogeneity within the compartments that comprise the mitochondrial network. Current dogma suggests that mtDNA replication is entirely dependent on expression of several nuclear-encoded factors such as the mtDNA polymerase. Despite functional heterogeneity within the mitochondrial network, compartment-specific autonomy over mtDNA regulation is rarely considered. In this proposal, we aim to understand how ATFS-1 establishes the appropriate amount mitochondrial mass during development, and maintains the mitochondrial network over an animals lifetime focusing on the separate activities of nuclear ATFS-1, and the fraction of ATFS-1 that accumulates in dysfunctional mitochondria and binds mtDNA. Lastly, we aim to understand the impact of an ATFS-1-mediated diapause that occurs if the mitochondrial network is severely damaged during development. At the end of the funding period, we hope to understand the endogenous strategies in place to establish and maintain the mitochondrial network, to potentially develop strategies to promote or maintain a robust mitochondrial network.

项目概要线粒体功能随衰老而下降，并在与年龄相关的疾病中加速，例如帕金森氏症和阿尔茨海默氏症。因此，了解细胞和生物体如何产生适当的发育过程中的线粒体质量，并认为衰老过程中线粒体网络是必不可少的限制与线粒体功能丧失相关的病理的步骤。在这里，我们的目的是了解转录因子 ATFS-1 和线粒体未折叠蛋白的潜在机制反应（UPRmt）协调正常发育和恢复过程中的线粒体网络生物发生通过线粒体区室中 ATFS-1 的独立调节功能来改变线粒体网络和细胞核。已鉴定出许多促进线粒体基因组复制的成分导致线粒体生物发生的核编码基因的转录。但目前尚不清楚在发育或细胞分化过程中如何获得适量的线粒体质量，以及线粒体网络如何在细胞或生物体的一生中维持。还未知是否线粒体基因组 (mtDNA) 复制与细胞生长、生理或功能协调构成线粒体网络的区室内的异质性。当前的教条表明线粒体DNA复制完全依赖于几种核编码因子的表达，例如线粒体DNA 聚合酶。尽管线粒体网络内的功能异质性，区室特异性线粒体 DNA 调控的自主性很少被考虑。在本提案中，我们旨在了解 ATFS-1 如何建立适当数量的线粒体发育过程中的质量，并在动物一生中维持线粒体网络，重点关注核 ATFS-1 的独立活性，以及在功能失调中积累的 ATFS-1 分数线粒体并结合 mtDNA。最后，我们的目标是了解 ATFS-1 介导的滞育的影响如果线粒体网络在发育过程中严重受损，就会发生这种情况。资助期结束时，我们希望了解建立和维持线粒体的内源性策略网络，有可能制定促进或维持强大的线粒体网络的策略。