Maintaining mitochondrial homeostasis during stress

应激期间维持线粒体稳态

• 批准号: RGPIN-2020-05204
• 负责人: Weidberg, Hilla
• 金额: $ 3.42万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746609
• 关键词: Maintaining; mitochondrial; homeostasis; during; stress

Mitochondria are essential organelles that provide cells with energy and numerous metabolites such as lipids, amino acids, iron-sulfur clusters, and heme. These organelles are semi-autonomous; they contain a genome but most of their proteome is encoded by the nucleus. Therefore, one of the most fundamental processes in maintaining mitochondrial functions is the import of proteins into the organelle. Protein import into the mitochondria is a complexed process, which can be challenged by cellular and environmental changes. Indeed, disturbances in mitochondrial protein import are common under physiological conditions such as oxidative stress, increased demand for energy, and aging. Although the mechanism governing protein import into mitochondria is well understood, little is known regarding how defects in this process are sensed and repaired by the cell. My long-term goal is to reveal how impaired mitochondrial protein import is repaired in budding yeast, both at the cellular and molecular levels. My previous studies showed that when protein import slows down, mitochondrial proteins accumulate in the import channels and clog the mitochondrial import machinery. I found that cells have evolved to cope with this stress by activating a transcriptional response - the mitochondrial compromised protein import response (mitoCPR). MitoCPR facilitates eviction of stalled proteins from the mitochondrial surface, and therefore restores mitochondrial functions during import stress. Many open questions remain regarding the roles and mechanisms of mitoCPR during import stress. Using a combination of biochemistry, genetics, and cell biology in yeast cells, my short-term research program will focus on two aims: 1. To elucidate the mitoCPR mechanisms of mitochondrial protein quality control; 2. To identify novel cellular pathways and factors that prevent mitochondrial damage during stress. In summary, my research program will advance our understanding of how proper mitochondrial functions are maintained, by revealing the mechanisms which control mitochondrial health. The essentiality of mitochondria in many metabolically active tissues and physiological processes is conserved across eukaryotes. Therefore, I envision a broad impact of this research on numerous scientific fields such as developmental biology, cell biology, and metabolism.

线粒体是重要的细胞器，为细胞提供能量和大量的代谢物，如脂类、氨基酸、铁硫簇和血红素。这些细胞器是半自主的；它们包含一个基因组，但它们的大部分蛋白质组由细胞核编码。因此，维持线粒体功能的最基本过程之一是将蛋白质输入细胞器。蛋白质进入线粒体是一个复杂的过程，可能会受到细胞和环境变化的挑战。事实上，线粒体蛋白输入的障碍在生理条件下是常见的，如氧化应激、能量需求增加和衰老。虽然控制蛋白质进入线粒体的机制已经被很好地理解了，但关于这个过程中的缺陷是如何被细胞感知和修复的知之甚少。我的长期目标是揭示在发芽酵母中受损的线粒体蛋白输入是如何在细胞和分子水平上修复的。我之前的研究表明，当蛋白质进口放缓时，线粒体蛋白质会在进口渠道中积累，并堵塞线粒体进口机制。我发现，细胞通过激活一种转录反应--线粒体妥协蛋白输入反应(MitoCPR)，进化出了应对这种压力的能力。MitoCPR有助于将停滞的蛋白质从线粒体表面驱逐出去，从而在进口应激期间恢复线粒体功能。关于有丝分裂细胞复苏在进口压力中的作用和机制，仍有许多悬而未决的问题。利用酵母细胞的生物化学、遗传学和细胞生物学相结合的方法，我的短期研究计划将集中在两个目标上：1.阐明线粒体蛋白质质量控制的mitoCPR机制；2.寻找新的细胞途径和因素，防止线粒体在应激中受损。总而言之，我的研究计划将通过揭示控制线粒体健康的机制，促进我们对线粒体如何维持正常功能的理解。线粒体在许多代谢活跃的组织和生理过程中的重要性在真核生物中是保守的。因此，我预计这项研究将对发育生物学、细胞生物学和新陈代谢等众多科学领域产生广泛影响。