Connexin30-deficient mice increase susceptibility to noise via redox and lactate imbalances.

Noise significantly contributes to one-third of the global burden of hearing loss. The intricate interplay of genetic and environmental factors impacts various molecular and cellular processes that lead to noise-induced hearing loss (NIHL). Defective connexin 26 (Cx26) and connexin 30 (Cx30), encoded by Gjb2/Cx26 and Gjb6/Cx30, respectively, are prevalent causes of hereditary deafness. However, the role of Cx30 in the pathogenesis of NIHL remains unclear. Herein, we observed that homozygous Cx30 knockout (Cx30 KO) mice exhibited poorer hearing recovery after noise exposure (97 dB mean sound pressure level for 2 h) and increased susceptibility to noise. In addition to the exacerbation of noise-induced damage to hair cells and synapses, Cx30 KO mice exposed to noise exhibited increased oxidative stress. The 2-(N-(7-nitrobenz-2-oxa-1,3-dia-zol-4-yl) amino)-2-deoxyglucose assay showed a reduction in glucose levels associated with a decrease in gap junctions as well as a reduction in adenosine triphosphate release. Glucose metabolomics analysis further revealed that Cx30 KO mice had elevated lactate and NAD  levels after noise exposure, thus worsening anaerobic oxidation from glycolysis. Our study emphasizes that Cx30-deficient mice increase susceptibility to noise via redox and lactate imbalances in the cochlea.