Coordinated Repair and Regeneration of Defective Mitochondria

项目摘要 线粒体功能在衰老过程中下降，并在与年龄相关的疾病中加速， 帕金森症和老年痴呆症。因此，了解细胞和生物体如何产生适当的 线粒体质量在发展和维持线粒体网络在老化是必不可少的 限制与线粒体功能丧失相关的病理的步骤。在这里，我们的目标是了解 转录因子ATFS-1和线粒体未折叠蛋白 在正常发育和恢复过程中，UPRmt反应（UPRmt）协调线粒体网络生物合成 通过ATFS-1在线粒体区室中的独立调节功能， 和原子核。 已经鉴定了许多促进线粒体基因组复制的组分， 核编码基因的转录导致线粒体生物发生。但尚不清楚 在发育或细胞特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。同样未知的是， 线粒体基因组（mtDNA）复制与细胞生长、生理或功能相协调 在构成线粒体网络的隔室内的异质性。目前的教条认为， mtDNA复制完全依赖于几种核编码因子的表达，如mtDNA 聚合酶。尽管线粒体网络内的功能异质性，但隔室特异性 线粒体DNA调控的自主性很少被考虑。 在这项提案中，我们的目标是了解ATFS-1如何建立适当数量的线粒体 质量在发展过程中，并维持线粒体网络在动物的一生，重点是 核ATFS-1的单独活性，以及在功能失调的细胞中积累的ATFS-1的部分， 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受到严重破坏，就会发生这种情况。在供资期结束时， 我们希望了解建立和维持线粒体的内源性策略， 网络，以潜在地开发策略，以促进或维持一个强大的线粒体网络。

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.