1. Academic Validation
  2. Autophagy impairment as a key feature for acetaminophen-induced ototoxicity

Autophagy impairment as a key feature for acetaminophen-induced ototoxicity

  • Cell Death Dis. 2021 Jan 4;12(1):3. doi: 10.1038/s41419-020-03328-6.
Tong Zhao 1 Tihua Zheng 1 Huining Yu 1 Bo Hua Hu 2 Bing Hu 3 Peng Ma 4 Ying Yang 1 Naidi Yang 5 Juan Hu 6 Tongtao Cao 1 Gang Chen 7 Bin Yan 1 Melina Peshoff 8 Maria Hatzoglou 9 Ruishuang Geng 10 Bo Li 11 Qing Yin Zheng 8
Affiliations

Affiliations

  • 1 Hearing and Speech Rehabilitation Institute, College of Special Education, Binzhou Medical University, Yantai, China.
  • 2 Center for Hearing and Deafness, University at Buffalo, Buffalo, NY, USA.
  • 3 Department of Otolaryngology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
  • 4 Department of Genetics, School of Pharmacy, Binzhou Medical University, Yantai, China.
  • 5 Key Laboratory of Flexible Electronics & Institute of Advanced Materials, Nanjing Tech University, Nanjing, China.
  • 6 Department of Otolaryngology-Head & Neck Surgery, Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, China.
  • 7 School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China.
  • 8 Department of Otolaryngology, Case Western Reserve University, Cleveland, OH, USA.
  • 9 Department of Genetics, Case Western Reserve University, Cleveland, OH, USA.
  • 10 Hearing and Speech Rehabilitation Institute, College of Special Education, Binzhou Medical University, Yantai, China. [email protected]
  • 11 Hearing and Speech Rehabilitation Institute, College of Special Education, Binzhou Medical University, Yantai, China. [email protected]
Abstract

Macroautophagy/Autophagy is a highly conserved self-digestion pathway that plays an important role in cytoprotection under stress conditions. Autophagy is involved in hepatotoxicity induced by acetaminophen (APAP) in experimental Animals and in humans. APAP also causes ototoxicity. However, the role of Autophagy in APAP-induced auditory hair cell damage is unclear. In the present study, we investigated Autophagy mechanisms during APAP-induced cell death in a mouse auditory cell line (HEI-OC1) and mouse cochlear explant culture. We found that the expression of LC3-II protein and autophagic structures was increased in APAP-treated HEI-OC1 cells; however, the degradation of SQSTM1/p62 protein, the yellow puncta of mRFP-GFP-LC3 fluorescence, and the activity of lysosomal enzymes decreased in APAP-treated HEI-OC1 cells. The degradation of p62 protein and the expression of lysosomal enzymes also decreased in APAP-treated mouse cochlear explants. These data indicate that APAP treatment compromises autophagic degradation and causes lysosomal dysfunction. We suggest that lysosomal dysfunction may be directly responsible for APAP-induced Autophagy impairment. Treatment with antioxidant N-acetylcysteine (NAC) partially alleviated APAP-induced Autophagy impairment and apoptotic cell death, suggesting the involvement of oxidative stress in APAP-induced Autophagy impairment. Inhibition of Autophagy by knocking down of Atg5 and Atg7 aggravated APAP-induced ER and oxidative stress and increased apoptotic cell death. This study provides a better understanding of the mechanism responsible for APAP ototoxicity, which is important for future exploration of treatment strategies for the prevention of hearing loss caused by ototoxic medications.

Figures
Products