Global Intracellular Responses to Mitophagy

项目概要 线粒体进行氧化磷酸化，为体内大多数细胞产生 ATP。的 受损或功能失调的线粒体的积累会导致多种人类疾病。 线粒体自噬是一种质量控制过程，可消除并回收受损的线粒体，以防止其 积累。大多数研究集中于线粒体自噬缺陷如何影响有丝分裂后细胞，因为第一个 确定了线粒体自噬基因的常染色体隐性突变导致神经退行性疾病，例如 帕金森氏症。然而，现在很清楚许多其他细胞类型也具有高水平的线粒体自噬活性。然而，我们 不了解线粒体自噬在这些情况下的重要性或影响。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，并可能使用线粒体自噬作为一种机制 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 和细胞分裂通过所需的细胞器间信号激酶密切相关，该激酶易位至任一 线粒体或中心体激活任一细胞过程。为了在未来五年内继续开展这项工作， 该提案将使用实时成像、遗传果蝇筛选、细胞生物学和生化方法， 转基因小鼠模型和原代干细胞回答以下问题：1）线粒体自噬是否存在缺陷 影响干细胞分裂和线粒体遗传？ 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传导类型 当其亚细胞定位决定时控制其他细胞过程？这项工作的广泛影响 将阐明为什么线粒体自噬基因在癌症等其他复杂疾病中发生突变，提供深入了解 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做出全球反应。

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.