Abstract
Aims: This study examined the effect of 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), an anion channel blocker of voltage-dependent anion channel 1 (VDAC1), on noise-induced hearing loss (NIHL) and its underlying mechanisms. Methods: Cochlear explants and House Ear Institute-Organ of Corti 1 (HEI-OC1) cells were used to assess the effect of DIDS in vitro. Auditory brainstem responses were used to assess auditory functions in mice. Immunofluorescence staining of myosin 7a and CTBP2 were used to examine hair cells and synaptic ribbons. The accumulation of reactive oxygen species (ROS) was measured by 4-HNE staining. The gene expression changes of cochlea were analyzed using RNA sequencing. Results: DIDS reduced the levels of ROS in cochlear explants and attenuated cell death caused by hydrogen peroxide in both cochlear explants and HEI-OC1 cells. In C57BL/6 mice, DIDS reduced ROS generation and tumor necrosis factor-α induced by noise exposure, thereby protecting outer hair cells and inner hair cell synaptic ribbons from noise-induced damage through a mechanism involving the PINK1/Parkin signaling pathway. The preventive effect of DIDS in cochlear explants was eliminated by mitophagy inhibition. Conclusion: VDAC1 inhibition enhances mitophagy in cochlear hair cells, playing a critical role in defending against oxidative stress and inflammation. Downregulation of VDAC1 may thus be considered a therapeutic strategy for preventing cochlear hair cell damage and reducing NIHL.