miR-34a/DRP-1-mediated mitophagy participated in cisplatin-induced ototoxicity via increasing oxidative stress

Abstract

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.

Comprehensive modular analyses of scar subtypes illuminate underlying molecular mechanisms and potential therapeutic targets

“…Such conditions frequently result from gene mutations and involve processes like skin development, keratinization and immune functions. Metabolism and oxidative stress mechanisms: PON2, DNM1L and VDAC2 are implicated in antioxidant responses and mitochondrial regulation. They could potentially be linked to metabolic skin diseases (like skin aging and metabolic syndrome) and skin disorders related to oxidative stress 80–82 …”

“…They could potentially be linked to metabolic skin diseases (like skin aging and metabolic syndrome) and skin disorders related to oxidative stress. [80][81][82] The Over Representation Analysis indicates that the package identified module M12 (Figure 5E). The top 14 genes were linked with two primary mechanisms: the Wnt signalling pathway and RNA splicing abnormalities mechanism.…”

Hesperidin activates Nrf2 to protect cochlear hair cells from cisplatin-induced damage

“…Regarding the cisplatin ototoxicity model, numerous studies have used systemic administration of cisplatin to induce hearing loss [ 27–29 ], while others have reported using transtympanic injection of cisplatin to simulate cisplatin-induced inner ear damage [ 18 ]. Although systemic administration of cisplatin better aligns with the clinical setting, the low survival rate and poor stability of mice due to the significant toxic side effects of cisplatin remain major challenges in this area of animal research [ 30 ].…”

NcRNA: key and potential in hearing loss

“…In other types of hearing loss, aberrant expression of miR-34a was also involved in disease progression. The overexpression of miR-34a inhibited DRP-1 expression and led to mitochondrial dysfunction as well as exacerbation of cisplatin-induced ototoxicity ( Wang et al, 2023 ). In the cochlea of db/db mice with diabetes mellitus, miR-34a was found to be significantly upregulated and accompanied by significant hearing threshold elevation and hair cell loss, implying that miR-34a could serve as a potential therapeutic target for diabetes-related hearing loss ( Lin et al, 2017 ; Figure 2 ).…”