2. Academic Validation
  3. Increased mitophagy protects cochlear hair cells from aminoglycoside-induced damage

Increased mitophagy protects cochlear hair cells from aminoglycoside-induced damage

  • Autophagy. 2022 Apr 26;1-17. doi: 10.1080/15548627.2022.2062872.
Yuhua Zhang 1,  Qiaojun Fang 1,  Hongfeng Wang 2,  Jieyu Qi 1,  Shan Sun 2,  Menghui Liao 1,  Yunhao Wu 1,  Yangnan Hu 1,  Pei Jiang 1,  Cheng Cheng 3 4,  Xiaoyun Qian 3 4,  Mingliang Tang 5,  Wei Cao 6,  Shang Xiang 7,  Chen Zhang 8,  Jianming Yang 6,  Xia Gao 3 4,  Zheng Ying 2,  Renjie Chai 1 8 9 10 11
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioelectronics, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, Jiangsu, China.
  • 2 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
  • 3 Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory), Nanjing, Jiangsu, China.
  • 4 Research Institute of Otolaryngology, Nanjing, Jiangsu, China.
  • 5 Institute for Cardiovascular Science & Department of Cardiovascular Surgery of the First Affiliated Hospital, Medical College, Soochow University, Suzhou, Jiangsu, China.
  • 6 Department of Otolaryngology Head and Neck Surgery, The Second Affiliated, Hospital of Anhui Medical University, Hefei, Anhui, China.
  • 7 High School Affiliated To Nanjing Normal University, Nanjing, Jiangsu, China.
  • 8 Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, China.
  • 9 Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • 10 Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China.
  • 11 Institute for Stem Cell and Regeneration, Chinese Academy of Science, Beijing, China.
PMID: 35471096 DOI: 10.1080/15548627.2022.2062872
Abstract

Aminoglycosides exhibit ototoxicity by damaging mitochondria, which in turn generate Reactive Oxygen Species that induce hair cell death and subsequent hearing loss. It is well known that damaged mitochondria are degraded by Mitophagy, an important mitochondrial quality control system that maintains mitochondrial homeostasis and ensures cell survival. However, it is unclear whether dysregulation of Mitophagy contributes to aminoglycoside-induced hair cell injury. In the current study, we found that PINK1-PRKN-mediated Mitophagy was impaired in neomycin-treated hair cells. Our data suggested that mitochondrial recruitment of PRKN and phagophore recognition of damaged mitochondria during Mitophagy were blocked following neomycin treatment. In addition, the degradation of damaged mitochondria by lysosomes was significantly decreased as indicated by the mitophagic flux reporter mt-mKeima. Moreover, we demonstrated that neomycin disrupted Mitophagy through transcriptional inhibition of Pink1 expression, the key initiator of Mitophagy. Moreover, we found that neomycin impaired Mitophagy by inducing ATF3 expression. Importantly, treatment with a Mitophagy Activator could rescue neomycin-treated hair cells by increasing Mitophagy, indicating that genetic modulation or drug intervention in Mitophagy may have therapeutic potential for aminoglycoside-induced hearing loss.

Keywords

ATF3; PRKN-PINK1; cell apoptosis; hair cells; kinetin; mitophagy; neomycin.

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