Inhibition of the mitochondrial permeability transition pore as a promising target for protecting auditory function in cisplatin-induced hearing loss

mPTP is a multi-protein complex that opens in mitochondria during cell death. Cisplatin-induced hearing loss is also known to be caused by mPTP opening. Thus, our study evaluated the protective effect of a novel mPTP inhibitor named DBP-iPT against cisplatin-induced hearing loss. The cell viability result showed that DBP-iPT provided a 40 % protective effect compared to the group treated with cisplatin. In addition, the DBP-iPT treated group exhibited a reduction in intracellular ROS levels, counteracting the excessive ROS accumulation induced by cisplatin at the whole cell level. Intriguingly, mitochondrial ROS levels in the DBP-iPT group were elevated three-fold compared to the cisplatin-treated group. Despite this increase in mitochondrial ROS, the mitochondrial membrane potential in the DBP-iPT group was three times higher than that of the control. These findings present intriguing contradictions to prior studies. Therefore, we investigated whether the mitochondria were damaged or not and found that DBP-iPT treatment maintained an increased portion of elongated mitochondria, suggesting autophagy-mediated removal of damaged mitochondria. This process leads to improved mitochondrial dynamics. Finally, in vivo studies confirmed that the ABR test using a mouse model showed the same pattern of protection against cisplatin-induced hearing loss in the DBP-iPT treatment group. We have identified a new target that has a protective effect against cisplatin-induced hearing loss. Therefore, this study is expected to provide valuable insights as it focuses on targeting mPTP opening to protect against ototoxicity caused by cisplatin. This discovery will serve as a significant foundation for future research. [Display omitted] •We investigated the previously unstudied associations between mPTP opening and cisplatin-induced hearing loss and identified a triazole derivative, DBP-iPT, as an mPTP inhibitor.•Cisplatin induces an increase in whole-cell ROS levels, whereas DBP-iPT only reduces intracellular ROS levels without affecting the reduction in mitochondrial ROS levels.•The elevation of mitochondrial calcium results from an increase in calcium capacity within the mitochondria due to mPTP inhibition, and cytosolic calcium levels are reduced as DBP-iPT prevents the opening of mPTP.•The mitochondrial functional study showed a high level of mitochondrial membrane potential and normal morphology of mitochondria, even though the mitochondrial ROS is elevated.•DBP-iPT effec