Global Intracellular Responses to Mitophagy

对线粒体自噬的整体细胞内反应

• 批准号: 10469574
• 负责人: Alicia M Pickrell
• 金额: $ 38.68万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-13 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10469574
• 关键词: Affect; Biochemical; Cell division; Cell physiology; Cells; Cellular biology; Centrosome; Cognition Disorders; Complex; Defect; Disease; Drosophila genus; Encephalitis; Ensure; Gene Proteins; Genes; Goals; Inflammation; Link; Longevity; Malignant Neoplasms; Mitochondria; Mitochondrial Inheritance; Mitotic; Mutate; Mutation; Neurodegenerative Disorders; Neurodevelopmental Disorder; Organelles; Oxidative Phosphorylation; Parkinson Disease; Phosphotransferases; Process; Quality Control; Signal Transduction; Transgenic Mice; Work; cell type; daughter cell; human disease; imaging genetics; insight; mitochondrial dysfunction; mouse model; prevent; response; stem cell division; stem cells

PROJECT SUMMARY Mitochondria perform oxidative phosphorylation to generate ATP for a majority of the cells in the body. The accumulation of damaged or dysfunctional mitochondria contribute to a wide range of human diseases. Mitophagy is a quality control process that eliminates and recycles damaged mitochondria to prevent their accumulation. A majority of studies focus on how mitophagy defects affect post-mitotic cells because the first identified autosomal recessive mutations in mitophagy genes caused neurodegenerative diseases such as Parkinson’s. However, it is now clear that many other cell types have high levels of mitophagic activity; yet, we do not understand the importance or impact of mitophagy in these contexts. For example, stem cells display high levels of mitophagy, divide continuously throughout their lifespan, and possibly use mitophagy as a mechanism to ensure daughter cells receive healthy mitochondria. Towards this goal, our findings support that mitophagy and cell division are intimately linked by a required interorganelle signaling kinase that translocates to either mitochondria or centrosomes to activate either cell process. To build upon this work within the next five years, this proposal will use live imaging, genetic drosophila screens, cell biology and biochemical approaches, transgenic mouse models, and primary stem cells to answer the following questions: 1) Do defects in mitophagy affect stem cell division and mitochondrial inheritance? 2) Can we identify other mitophagy proteins/genes that influence cell division? 3) Does the type of interorganelle signaling that connects mitophagy and cell division control other cellular processes when dictated by its subcellular localization? The broad implications of this work will elucidate why mitophagy genes are mutated in other complex diseases such as cancer, provide insight into how mitochondrial dysfunction affects stem cells contributing to neurodevelopmental and cognitive disorders, and define fundamental signaling interactions between organelles to deepen our understanding of how cells globally respond to dysfunctional mitochondria.

项目摘要 线粒体进行氧化磷酸化，为体内大多数细胞产生ATP。的 受损或功能障碍的线粒体的积累导致多种人类疾病。 线粒体自噬是一种质量控制过程，其消除和修复受损的线粒体以防止其 积累大多数研究集中在有丝分裂缺陷如何影响有丝分裂后细胞，因为第一个缺陷是细胞分裂。 线粒体自噬基因中确定的常染色体隐性突变引起神经退行性疾病， 帕金森等然而，现在清楚的是，许多其他细胞类型具有高水平的线粒体吞噬活性;然而，我们 不理解线粒体自噬在这些背景下的重要性或影响。例如，干细胞表现出高 线粒体自噬水平，在其整个生命周期中不断分裂，并可能将线粒体自噬作为一种机制， 以确保子细胞获得健康的线粒体。为了实现这一目标，我们的研究结果支持线粒体自噬 和细胞分裂密切相关的细胞器间所需的信号激酶， 线粒体或中心体来激活任一细胞过程。为了在今后五年内在这项工作的基础上再接再厉， 这项提议将使用活体成像、果蝇基因筛选、细胞生物学和生物化学方法， 转基因小鼠模型和原代干细胞来回答以下问题：1）线粒体自噬缺陷 影响干细胞分裂和线粒体遗传吗2)我们能否鉴定出其他线粒体自噬蛋白/基因， 影响细胞分裂？3)连接线粒体自噬和细胞分裂的细胞器间信号 控制其他细胞过程时，由其亚细胞定位？这项工作的广泛影响 将阐明为什么线粒体自噬基因在其他复杂疾病如癌症中发生突变， 线粒体功能障碍如何影响导致神经发育和认知障碍的干细胞， 并定义细胞器之间的基本信号相互作用，以加深我们对细胞如何 对功能失调的线粒体有反应