Disruption of Hars2 in Cochlear Hair Cells Causes Progressive Mitochondrial Dysfunction and Hearing Loss in Mice

This study investigated the effects of Hars2 gene disruption in mouse cochlear hair cells, which is linked to Perrault syndrome 2 (PRLTS2) and hearing loss. The targeted knockout of Hars2 led to progressive hearing loss starting at postnatal day 30 (P30), with significant hair cell loss observed from P45. This was associated with elevated reactive oxygen species (ROS) levels and activation of the mitochondrial apoptotic pathway. Despite normal ribbon synapse formation, there was reduced calcium influx and compromised synaptic exocytosis in inner hair cells, correlating with decreased auditory brainstem response amplitudes. Mitochondrial abnormalities, such as swelling and loss of cristae, were noted from P14, with outer hair cells experiencing more severe loss. The findings indicated that Hars2 knockout caused mitochondrial dysfunction and ROS stress, leading to hair cell synaptopathy and apoptosis, affecting inner and outer hair cells differently.