Mechanisms of Mitochondrial Degradation in Unstressed Mammalian Cells

项目摘要/摘要 线粒体在一组大分子的能量产生和生物合成中起着重要作用。 是真核生物生存所必需的。它们还拥有潜在危险的细胞内机器，能够 产生氧化损伤，触发炎症信号，并启动程序性细胞死亡。 线粒体动态平衡对于维持健康的代谢活跃的线粒体池和 避免因不断恶化的线粒体积累而造成的细胞损伤。其中一个关键组件 线粒体动态平衡是对陈旧的、受损的或多余的线粒体的选择性降解。近期 努力已经非常详细地阐明了通过实验损伤的分子机制 在表达Parkin的真核细胞中，线粒体被降解。然而，很明显，哺乳动物细胞也 通过偶联的新线粒体的生物发生来不断更新线粒体内容 即使在没有外源损伤的情况下，旧的线粒体也会降解。控制这一点的机制 人们对线粒体正在发生的更替知之甚少。这一提议旨在阐明信号转导 在非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 了解线粒体基础降解在细胞适应和应激中的作用的切入点 抵抗。这将通过回答三个关键问题来实现：1)什么控制着 线粒体周转在没有外源性损伤的情况下？2)在没有外源性损伤的情况下，如何 线粒体是被选择来降解的吗？3)这条途径在发育编程中扮演什么角色 线粒体清除？这些问题将使用分子和遗传技术在 生物化学、细胞和生物标尺。回答这些问题将为以下方面提供实质性的见解 基本细胞生物学过程的机械细节和生理作用。这项工作将会有所改进 对正常发育和动态平衡以及各种人类疾病的病因的理解 线粒体的动态平衡可以保护其免受。

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.