ATP depletion induced cochlear hair cells death through histone deacetylation in vitro.

Previous studies have shown histone modifications being present in cochlear hair cells in animal models of hearing loss. Our past studies have shown that ATP depletion, histone deacetylase (HDAC) upregulation, and histone deacetylation occur in cochlea after noise exposure, and these are linked to hair cell death. Whether ATP depletion correlates with the expression level of HDACs and acetylation of histones is still unknown. In this study, we investigated the changes in the expression of HDACs and the level of histone acetylation in cochlear hair cells using an ATP-depleted explant culture of mouse organ of Corti. We found that the expression of HDAC3 and HDAC6 increased and hair cells were lost after oligomycin A (OA) treatment. Meanwhile, the acetylation level of histone H2B reduced. However, when oligomycin was combined with an HDAC inhibitor, trichostatin A (TSA), the acetylation level of histone H3 was restored. Moreover, combined treatment of oligomycin and TSA or sodium butyrate (NaB) attenuated oligomycin-induced cochlear hair cell loss. In conclusion, our results indicated that ATP depletion led to histone deacetylation and eventually resulted in hair cell death.