Mechanisms of Mitochondrial Degradation in Unstressed Mammalian Cells

项目总结/摘要 线粒体在能量产生和一系列大分子生物合成中起着重要作用 是真核生物所必需的它们还具有潜在危险的细胞内机制， 产生氧化损伤、触发炎症信号传导和启动程序性细胞死亡。 线粒体内稳态对于维持代谢活性线粒体的健康库是至关重要的， 避免了由恶化的线粒体的积累引起的细胞损伤。一个关键组成部分， 线粒体稳态是选择性降解陈旧的、受损的或多余的线粒体。最近 已经详细阐明了实验性损伤的分子机制， 线粒体在表达Parkin的真核细胞中被降解。然而，很明显，哺乳动物细胞也 通过新线粒体的生物发生， 老化线粒体的降解，即使在没有外源性损伤的情况下。控制这一点的机制 线粒体的持续更新知之甚少。该建议旨在阐明信号转导 在未应激的哺乳动物细胞中驱动线粒体降解的途径，并将该途径用作 了解基础线粒体降解在细胞适应和应激中所起作用的切入点 阻力这将通过回答三个关键问题来实现：1）是什么控制了 在没有外源性损伤的情况下，线粒体的周转率如何？2)在没有外源性损伤的情况下， 线粒体是否被选择降解？3)这条通路在发育程序化的 线粒体清除率这些问题将使用分子和遗传技术来回答， 生物化学、细胞和有机体尺度。探讨这些问题将提供实质性的见解， 基本细胞生物学过程的机械细节和生理作用。这项工作将得到改善 了解正常发育和体内平衡以及各种人类疾病的病因 线粒体内环境稳定的保护。

Project Summary/Abstract Mitochondria play essential roles in energy production and biosynthesis of a subset of macromolecules necessary for eukaryotic life. They also house potentially dangerous intracellular machinery capable of generating oxidative damage, triggering inflammatory signaling, and initiating programmed cell death. Mitochondrial homeostasis is critical for maintaining a healthy pool of metabolically active mitochondria and avoiding cellular damage caused by the accumulation of deteriorating mitochondria. One key component of mitochondrial homeostasis is the selective degradation of old, damaged, or superfluous mitochondria. Recent efforts have elucidated in great detail the molecular mechanisms through which experimentally damaged mitochondria are degraded in Parkin-expressing eukaryotic cells. However, it is clear that mammalian cells also undergo constant renewal of mitochondrial content through biogenesis of new mitochondria coupled to degradation of old mitochondria, even in the absence of exogenous damage. The mechanisms controlling this ongoing mitochondrial turnover are poorly understood. This proposal aims to illuminate the signal transduction pathway that drives mitochondrial degradation in unstressed mammalian cells, and to use this pathway as an entry point to understand the roles that basal mitochondrial degradation plays in cellular adaptation and stress resistance. This will be accomplished by answering three key questions: 1) What controls the rate of mitochondrial turnover in the absence of exogenous damage? 2) In the absence of exogenous damage, how are mitochondria selected for degradation? 3) What role does this pathway play in developmentally programmed mitochondrial clearance? These questions will be answered using molecular and genetic techniques on the biochemical, cellular, and organismal scales. Answering these questions will provide substantial insights into the mechanistic details and physiological roles of a fundamental cell biological process. This work will improve understanding of normal development and homeostasis as well as the etiologies of diverse human diseases against which mitochondrial homeostasis protects.