Activated mTORC1 signaling pathway aggravates cisplatin induced oxidative damage by inhibiting autophagy in mouse cochlear hair cells

Abstract

Platinum-based antitumor drugs, such as cisplatin and carboplatin, are well-known for their severe ototoxicity. The ototoxic effects of these drugs are primarily attributed to oxidative stress induced damage within cochlear hair cells (HCs), leading to cell death and subsequent irreversible hearing loss. Over the past decade, studies have demonstrated that upregulating autophagy levels in HCs can greatly alleviate the death of cochlear HCs as part of the oxidative damage induced by ototoxic drugs. However, the molecular mechanisms by which platinum-based drugs affect autophagy and ultimately lead to HCs death remain unclear. In the present study, we investigated the effects of cisplatin on the mTOR signaling pathway, a critical regulator of autophagy, in cochlear explants of mice. Our results indicated that while cisplatin enhances autophagy activity initially, it also activates mTOR Complex1 (mTORC1) within HCs. The persistent activation of mTORC1 inhibits autophagy in HCs, resulting in the accumulation of reactive oxygen species and leading to cell death. Further pharmacological experiments confirmed the protective role of rapamycin, a specific mTORC1 inhibitor, highlighting the importance of autophagy in combating cisplatin-induced ototoxicity. Our findings suggest that modulating the mTOR signaling pathway to regulate autophagy could be an effective strategy for preventing cisplatin-induced ototoxic damage.