The excessive generation of reactive oxygen species (ROS) and mitochondrial damage have been widely reported in noise-induced hearing loss (NIHL). However, the specific mechanism of noise-induced mitochondrial damage remains largely unclear. In this study, we showed that acoustic trauma caused oxidative damage to mitochondrial DNA (mtDNA), leading to the reduction of mtDNA content, mitochondrial gene expression and ATP level in rat cochleae. The expression level and mtDNA-binding function of mitochondrial transcription factor A (TFAM) were impaired following acoustic trauma without affecting the upstream PGC-1α and NRF-1. The mitochondria-target antioxidant mito-TEMPO (MT) was demonstrated to enter the inner ear after the systemic administration. MT treatment significantly alleviated noise-induced auditory threshold shifts 3d and 14d after noise exposure. Furthermore, MT significantly reduced outer hair cell (OHC) loss, cochlear ribbon synapse loss, and auditory nerve fiber (ANF) degeneration after the noise exposure. In addition, we found that MT treatment effectively attenuated noise-induced cochlear oxidative stress and mtDNA damage, as indicated by DHE, 4-HNE, and 8-OHdG. MT treatment also improved mitochondrial biogenesis, ATP generation, and TFAM-mtDNA interaction in the cochlea. These findings suggest that MT has protective effects against NIHL via maintaining TFAM-mtDNA interaction and mitochondrial biogenesis based on its ROS scavenging capacity.

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Hair cell death induced by excessive reactive oxygen species (ROS) has been identified as the major pathogenesis of noise-induced hearing loss (NIHL). Recent studies have demonstrated that cisplatin- and neomycin-induced ototoxicity can be alleviated by ferroptosis inhibitors. However, whether ferroptosis inhibitors have a protective effect against NIHL remains unknown. We investigated the protective effect of the ferroptosis inhibitor ferrostatin-1 (Fer-1) on NIHL in vivo in CBA/J mice and investigated the protective effect of Fer-1 on tert-butyl hydroperoxide (TBHP)-induced hair cell damage in vitro in cochlear explants and HEI-OC1 cells. We observed ROS overload and lipid peroxidation, which led to outer hair cell (OHC) apoptosis and ferroptosis, in the mouse cochlea after noise exposure. The expression level of apoptosis-inducing factor mitochondria-associated 2 (AIFM2) was substantially increased following elevation of the expression of its upstream protein P53 after noise exposure. The ferroptosis inhibitor Fer-1was demonstrated to enter the inner ear after the systemic administration. Administration of Fer-1 significantly alleviated noise-induced auditory threshold elevation and reduced the loss of OHCs, inner hair cell (IHC) ribbon synapses, and auditory nerve fibers (ANFs) caused by noise. Mechanistically, Fer-1 significantly reduced noise- and TBHP-induced lipid peroxidation and iron accumulation in hair cells, alleviating ferroptosis in cochlear cells consequently. Furthermore, Fer-1 treatment decreased the levels of TfR1, P53, and AIFM2. These results suggest that Fer-1 exerted its protective effects by scavenging of ROS and inhibition of TfR1-mediated ferroptosis and P53-AIFM2 signaling pathway-mediated apoptosis. Our findings suggest that Fer-1 is a promising drug for treating NIHL because of its ability to inhibit noise-induced hair cell apoptosis and ferroptosis, opening new avenues for the treatment of NIHL.

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Cisplatin is a well-known and widely used anticancer drug with high therapeutic efficacy in solid tumors; however, side effects are common with its use. Because cisplatin can be retained in the cochlea, ototoxicity leading to hearing loss limits its clinical applications. Here, we report that Nrf2 knockout (KO) strongly increased cisplatin resistance in HEI-OC1 cells, which are immortalized cells from the murine organ of Corti. The underlying mechanism of this phenomenon was uncovered, and an important novel therapeutic target for combating cisplatin-induced hearing loss was identified. Preliminary investigations determined that Nrf2 KO markedly decreased TfR1 protein levels and increased GPX4 protein levels. Thus, ferroptosis may protect organisms from cisplatin-induced cell death. Furthermore, Nrf2 KO cells were resistant to the classical ferroptosis inducers RSL3 and erastin, providing solid evidence that Nrf2 KO inhibits ferroptosis and that knocking out Nrf2 may be a new clinical strategy to prevent cisplatin-induced hearing loss.