Mitophagy Impairment Aggravates Cisplatin-Induced Ototoxicity

Area of Science:

• Cell Biology
• Ototoxicity Research
• Mitochondrial Dynamics

Background:

• Cisplatin is a vital chemotherapy drug, but its use is limited by ototoxicity, leading to irreversible hearing loss.
• Cisplatin-induced ototoxicity is linked to oxidative stress and mitochondrial damage within cochlear cells.
• Mitophagy plays a crucial role in maintaining mitochondrial health and cellular energy balance.

Purpose of the Study:

• To investigate the role of mitophagy in protecting against cisplatin-induced ototoxicity.
• To analyze the impact of modulating mitophagy on the viability and mitochondrial function of auditory cells exposed to cisplatin.

Main Methods:

• HEI-OC1 auditory cells were treated with cisplatin alone, or in combination with mitophagy inhibitors (3-MA) or promoters (CCCP).
• Gene silencing of mitophagy-associated proteins (Parkin, BNIP3) was performed using small-interfering RNAs.
• Cell viability (WST assay), mitophagy marker expression (Western blot), mitochondrial membrane potential (flow cytometry), and ATP levels (spectrophotometry) were assessed.

Main Results:

• Cisplatin exposure reduced cell viability, depolarized mitochondria, decreased ATP levels, and increased mitophagy markers (PINK1, Parkin, BNIP3, p62, LC3B).
• Knockdown of Parkin or BNIP3 exacerbated cisplatin-induced cell death and mitochondrial dysfunction.
• Inhibiting mitophagy with 3-MA worsened cisplatin cytotoxicity, while promoting mitophagy with CCCP offered protection.

Conclusions:

• Mitophagy plays a protective role in HEI-OC1 cells against cisplatin-induced ototoxicity.
• Targeted promotion of mitophagy may represent a therapeutic strategy to mitigate cisplatin-induced hearing loss.