Absence of oncomodulin increases susceptibility to noise-induced outer hair cell death and alters mitochondrial morphology

Cochlear outer hair cells (OHCs) play a fundamental role in the hearing sensitivity and frequency selectivity of mammalian hearing and are especially vulnerable to noise-induced damage. The OHCs depend on Ca²⁺ homeostasis, which is a balance between Ca²⁺ influx and extrusion, as well as Ca²⁺ buffering by proteins and organelles. Alterations in OHC Ca²⁺ homeostasis is not only an immediate response to noise, but also associated with impaired auditory function. However, there is little known about the contribution of Ca²⁺ buffering proteins and organelles to the vulnerability of OHCs to noise. In this study, we used a knockout (KO) mouse model where oncomodulin (<i>Ocm</i>), the major Ca²⁺ binding protein preferentially expressed in OHCs, is deleted. We show that <i>Ocm</i> KO mice were more susceptible to noise induced hearing loss compared to wildtype (WT) mice. Following noise exposure (106 dB SPL, 2 h), <i>Ocm</i> KO mice had higher threshold shifts and increased OHC loss and TUNEL staining, compared to age-matched WT mice. Mitochondrial morphology was significantly altered in <i>Ocm</i> KO OHCs compared to WT OHCs. Before noise exposure, <i>Ocm</i> KO OHCs showed decreased mitochondrial abundance, volume, and branching compared to WT OHCs, as measured by immunocytochemical staining of outer mitochondrial membrane protein, TOM20. Following noise exposure, mitochondrial proteins were barely visible in <i>Ocm</i> KO OHCs. Using a mammalian cell culture model of prolonged cytosolic Ca²⁺ overload, we show that OCM has protective effects against changes in mitochondrial morphology and apoptosis. These experiments suggest that disruption of Ca²⁺ buffering leads to an increase in noise vulnerability and mitochondrial-associated changes in OHCs.