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.
Mutations that affect mitochondria often result in hearing loss. We propose experiments using the zebrafish lateral line system to describe how mitochondrial metabolism responds to hair cell mechanical stimuli, and to assess the remarkable mitochondrial biogenesis that occurs as hair cells develop. We will generate mutations in zebrafish to model human syndromes, and assess their functional consequences on mitochondrial biogenesis and metabolism.
|Schrauwen, Isabelle; Kari, Elina; Mattox, Jacob et al. (2018) De novo variants in GREB1L are associated with non-syndromic inner ear malformations and deafness. Hum Genet 137:459-470|