Global Intracellular Responses to Mitophagy

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.