Purpose Cisplatin is a widely used and effective chemotherapeutic agent for most solid malignant tumors. However, cisplatin-induced ototoxicity is a common adverse effect that limits the therapeutic efficacy of tumors in the clinic. To date, the specific mechanism of ototoxicity has not been fully elucidated, and the management of cisplatin-induced ototoxicity is also an urgent challenge. Recently, some authors believed that miR34a and mitophagy played a role in age-related and drug-induced hearing loss. Our study aimed to explore the involvement of miR-34a/DRP-1-mediated mitophagy in cisplatin-induced ototoxicity. Methods In this study, C57BL/6 mice and HEI-OC1 cells were treated with cisplatin. MiR-34a and DRP-1 levels were analyzed by qRT‒PCR and western blotting, and mitochondrial function was assessed via oxidative stress, JC-1 and ATP content. Subsequently, we detected DRP-1 levels and observed mitochondrial function by modulating miR-34a expression in HEI-OC1 cells to determine the effect of miR-34a on DRP-1-mediated mitophagy. Results MiR-34a expression increased and DRP-1 levels decreased in C57BL/6 mice and HEI-OC1 cells treated with cisplatin, and mitochondrial dysfunction was involved in this process. Furthermore, the miR-34a mimic decreased DRP-1 expression, enhanced cisplatin-induced ototoxicity and aggravated mitochondrial dysfunction. We further verified that the miR-34a inhibitor increased DRP-1 expression, partially protected against cisplatin-induced ototoxicity and improved mitochondrial function. Conclusion MiR-34a/DRP-1-mediated mitophagy was related to cisplatin-induced ototoxicity and might be a novel target for investigating the treatment and protection of cisplatin-induced ototoxicity.

Purpose Cisplatin is a widely and effectively chemotherapy agent for most of solid malignant tumors. However,cisplatin induced ototoxicity is a common adverse effect,which limited the therapeutic efficacy of tumors in clinic.To date,the specific mechanism of ototoxicity is not fully elucidated and the management of cisplatin-induced ototoxicity also is an urgent challenge.Recently,some authors believed that miR34a and mitophagy played a role in age-related and drug-induced hearing loss.Our study is aimed at exploring the involvement of miR-34a/DRP-1 mediated mitophagy on cisplatin-induced ototoxicity. Methods In this study,C57BL/6 mices and HEI-OC1 cells were treated with cisplatin,miR-34a and DRP-1 level was analyzed by qRT-PCR and western blot,and assessed mitochondrial function via oxidative stress,JC-1 and ATP content.Subsequently,we detected DRP-1 level and observed mitochondrial function through modulating miR-34a expression in HEI-OC1 cells,to determine the effect of miR-34a on DRP-1 mediated mitophagy. Results MiR-34a expression increased and DRP-1 level decreased in C57BL/6 mice and HEI-OC1 cell treated with cisplatin,and mitochondria dysfunction was involved in the process.Furthermore,miR-34a mimic decreased DRP-1 expression,enhanced cisplatin-induced ototoxicity and aggravated mitochondrial dysfunction.We further verified that miR-34a inhibitor increased DRP-1 expression, partially protected aganist cisplatin-induced ototoxicity and improved mitochondrial function. Conclusion MiR-34a/DRP-1-mediated mitophagy was related to cisplatin induced ototoxicity and might be a novel target for investigating the treatement and protection of cisplatin-induced ototoxicity.