Mitochondrial function and dysfunction in hair cells

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PROJECT SUMMARY Genetic disruptions of over thirty genes affecting mitochondrial functions result in hearing loss. We propose to understand the cellular consequences of representative mutations in mechanosensory hair cells. Our preliminary studies demonstrate that hair cells undergo rapid mitochondrial biogenesis as they mature, and that mitochondria actively respond to mechanosensory cues. We propose studies to understand the regulation of mitochondrial growth and function, focusing on the roles of specialized connections between mitochondria and the endoplasmic reticulum (ER). Growing evidence supports a role for ER-mitochondrial junctions regulating mitochondrial metabolism, dynamics, and stress and for playing a central role in regulated cell death. We propose experiments using live imaging of hair cells in the zebrafish lateral line, a system amenable to study of cellular functions in vivo. We will assess mitochondrial growth, oxidation and ATP utilization in hair cells, and determine the consequences of disrupting ER-mitochondrial communication. We will measure changes in mitochondria in response to mechanical stimuli. Using CRISPR, we will generate zebrafish models of human mitochondrial mutations to assess functional consequences for hair cells. Our experiments will reveal potentially fundamental mechanisms of mitochondria in hair cells and how these mechanisms go awry in human hearing loss.