2. Academic Validation
  3. Inhibition of CISD1 attenuates cisplatin-induced hearing loss in mice via the PI3K and MAPK pathways

Inhibition of CISD1 attenuates cisplatin-induced hearing loss in mice via the PI3K and MAPK pathways

  • Biochem Pharmacol. 2024 Mar 14:116132. doi: 10.1016/j.bcp.2024.116132.
Wenqi Dong 1,  Yumeng Jiang 1,  Qinxiu Yao 2,  Maoxiang Xu 3,  Yuchen Jin 1,  Lingkang Dong 1,  Zhuangzhuang Li 4,  Dongzhen Yu 5
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head and Neck Surgery, Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Department of Otolaryngology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 3 Department of ORL-HNS, Shanghai Fourth People's Hospital, and School of Medicine, Tongji University, Shanghai, China.
  • 4 Shanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head and Neck Surgery, Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: drzhuangzhuang@163.com.
  • 5 Shanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head and Neck Surgery, Otolaryngology Institute of Shanghai Jiao Tong University, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: 7250012023@shsmu.edu.cn.
PMID: 38492782 DOI: 10.1016/j.bcp.2024.116132
Abstract

Cisplatin is an effective chemotherapeutic drug for different cancers, but it also causes severe and permanent hearing loss. Oxidative stress and mitochondrial dysfunction in cochlear hair cells (HCs) have been shown to be important in the pathogenesis of cisplatin-induced hearing loss (CIHL). CDGSH iron sulfur domain 1 (CISD1, also termed mitoNEET) plays a critical role in mitochondrial oxidative capacity and cellular bioenergetics. Targeting CISD1 may improve mitochondrial function in various diseases. However, the role of CISD1 in cisplatin-induced ototoxicity is unclear. Therefore, this study was performed to assess the role of CISD1 in cisplatin-induced ototoxicity. We found that CISD1 expression was significantly increased after cisplatin treatment in both HEI-OC1 cells and cochlear HCs. Moreover, pharmacological inhibition of CISD1 with NL-1 inhibited cell Apoptosis and reduced mitochondrial Reactive Oxygen Species in HEI-OC1 cells and cochlear explants. Inhibition of CISD1 with small interfering RNA in HEI-OC1 cells had similar protective effects. Furthermore, NL-1 protected against CIHL in adult C57 mice, as evaluated by the auditory brainstem response and immunofluorescent staining. Mechanistically, RNA Sequencing revealed that NL-1 attenuated CIHL via the PI3K and MAPK pathways. Most importantly, NL-1 did not interfere with the antitumor efficacy of cisplatin. In conclusion, our study revealed that targeting CISD1 with NL-1 reduced Reactive Oxygen Species accumulation, mitochondrial dysfunction, and Apoptosis via the PI3K and MAPK pathways in HEI-OC1 cell lines and mouse cochlear explants in vitro, and it protected against CIHL in adult C57 mice. Our study suggests that CISD1 may serve as a novel target for the prevention of CIHL.

Keywords

CISD1; Cisplatin; Hair cell; MAPK; NL-1; PI3K.

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