Global Intracellular Responses to Mitophagy

对线粒体自噬的整体细胞内反应

• 批准号: 10264447
• 负责人: Alicia M Pickrell
• 金额: $ 38.41万
• 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/10264447
• 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 线粒体执行氧化磷酸化，以生成体内大多数细胞的ATP。这 损害或功能障碍线粒体的积累会导致广泛的人类疾病。 线粒体是一个质量控制过程，可消除并回收损坏的线粒体，以防止其 积累。大多数研究都集中于线粒体缺陷如何影响降解后细胞，因为第一个 线粒体基因中鉴定的常染色体隐性突变引起神经退行性疾病，例如 帕金森氏症。但是，现在很明显，许多其他细胞类型具有高水平的线粒体活性。但是，我们 在这些情况下不了解线粒体的重要性或影响。例如，干细胞显示高 线粒体的水平，在整个生命周期中连续分裂，并可能使用线粒体作为一种机制 确保子细胞获得健康的线粒体。达到这个目标，我们的发现支持了线粒体 和细胞分裂通过所需的跨加工信号激酶密切相关，该激酶易位 线粒体或中心体激活任何一个细胞过程。为了在未来五年内建立这项工作， 该建议将使用实时成像，遗传性滴虫筛选，细胞生物学和生化方法， 转基因小鼠模型和主要干细胞回答以下问题：1）在线粒体中确实存在缺陷 影响干细胞分裂和线粒体遗传？ 2）我们可以识别其他线索蛋白/基因 影响细胞分裂？ 3）是否有连接线粒体和细胞分裂的机管机间信号传导 在其亚细胞定位决定时控制其他细胞过程？这项工作的广泛含义 会阐明为什么线粒体基因在其他复杂疾病（例如癌症）中突变的原因，可以洞悉 线粒体功能障碍如何影响有助于神经发育和认知疾病的干细胞， 并定义细胞器之间的基本信号相互作用，以加深我们对细胞的理解 全球对线粒体功能失调的反应。