Mitochondria actively generate ATP via oxidative phosphorylation and constantly undergo high levels of oxidative stress. Lysosomal degradation of mitochondria is a key quality control that inhibits the accumulation of mitochondrial damage. Understanding mitochondrial quality control is critical and urgent because its defects have been linked to many neurological disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Our preliminary data led us to hypothesize that a brain-specific, lysosome- associated isoform of Drp1 GTPase, termed lysoDrp1, enhances transport of mitochondria to lysosomes by increasing the proximity between these two organelles. In this proposed investigation, we will test this hypothesis in two specific aims. In the first aim, we will determine how lysoDrp1 delivers mitochondria into lysosomes (1.1), how GTP regulates lysoDrp1 (1.2), and what recruits lysoDrp1 to lysosomes (1.3). In the second aim, we will determine the function of lysoDrp1 in mitochondrial turnover in neurons (2.1), the role of lysoDrp1-meidated quality control for energy metabolism in neurons (2.2), and the impact of lysoDrp1 on the survival of neurons (2.3). To successfully accomplish these aims, we will use innovative approaches including lysoDrp1-specific mouse knockout generated by CRISPR/Cas9, a fluorescent biosensor for the transport of mitochondria to lysosomes and Drp1-knockout cells reconstituted with single, specific Drp1 isoforms. This work will have a significant impact on translating the mechanistic information of mitochondrial quality control into therapeutic interventions for human diseases.
Abnormalities in mitochondrial degradation are associated with many neurodegenerative diseases. This proposal is aimed at determining the mechanism, regulation and function of the novel mitochondrial quality control pathway mediated by lysoDrp1, providing significant insight into human health and diseases.
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