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，如 帕金森氏症和阿尔茨海默氏症。因此，了解细胞和有机体如何产生适当的 线粒体在发育过程中的质量和在衰老过程中维持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改变。在这里，我们的目标是了解 转录因子ATFS-1和线粒体去折叠蛋白的潜在机制 反应(UPRmt)协调正常发育和恢复过程中线粒体网络的生物发生 通过线粒体间隔中ATFS-1的独立调节功能对线粒体网络的影响 和细胞核。 已经确定了许多促进线粒体基因组复制的成分和 导致线粒体生物发生的核编码基因的转录。然而，目前仍不清楚 在发育或细胞规格过程中如何达到适当数量的线粒体质量，以及 线粒体网络是如何在细胞或生物体的生命周期中维持的。目前还不清楚是否 线粒体基因组(MtDNA)复制与细胞生长、生理或功能相协调 组成线粒体网络的隔室内的异质性。目前的教条表明 线粒体DNA复制完全依赖于几种核编码因子的表达，如线粒体DNA 聚合酶。尽管线粒体网络中的功能异质性，但具有间隔性 线粒体DNA调控的自主性很少被考虑。 在这个方案中，我们旨在了解ATFS-1是如何建立适当数量的线粒体的 在发育过程中大量存在，并在动物一生中维持线粒体网络，专注于 核ATFS-1的单独活性，以及在功能障碍中积累的ATFS-1的部分 线粒体与线粒体DNA结合。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。 潜在地制定促进或维持强大的线粒体网络的战略。

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.