The role of calcium homeostasis in the function and dysfunction of cochlear outer hair cells.

Cochlear outer hair cells (OHCs) are uniquely vulnerable to both extrinsic and intrinsic cellular insults. Calcium signaling is important for OHC function. However, calcium dysregulation leads to OHC stress and subsequent death. Oncomodulin (OCM) is an EF-hand calcium-binding protein found in the mammalian cochlea. Deletion of OCM (Ocm KO) leads to a plethora of cellular disruptions that eventually result in early onset hearing loss. The overarching goal of these studies was to explore the cellular mechanisms that are involved in calcium-related stress in OHCs. Through cell culture experiments, we determined that OCM buffered calcium differently than two other physiologically relevant calcium-binding proteins. We used Ocm KO mice to magnify the consequences of calcium dysregulation in the inner ear. We found that during development, loss of OCM resulted in dysregulated calcium signaling starting at postnatal day 3. While Ocm KO OHCs continue to develop normally, continuous dysregulation of calcium results in a hearing loss phenotype in adult Ocm KO mice. Ocm KO mice are more susceptible to OHC loss following noise exposure. Additionally, Ocm KO mice had a reduced number of mitochondria, with and without noise exposure. While wildtype mice responded to noise exposure by upregulating pro-survival genes, Ocm KO mice had hallmarks of apoptosis. Through these experiments, we have determined that OCM protects OHCs against mitochondrial calcium overload through its unique buffering capabilities.