Increased mitophagy protects cochlear hair cells from aminoglycoside-induced damage

被引:49
作者
Zhang, Yuhua [1 ]
Fang, Qiaojun [1 ]
Wang, Hongfeng [2 ,3 ]
Qi, Jieyu [1 ]
Sun, Shan [2 ,3 ]
Liao, Menghui [1 ]
Wu, Yunhao [1 ]
Hu, Yangnan [1 ]
Jiang, Pei [1 ]
Cheng, Cheng [4 ,5 ]
Qian, Xiaoyun [4 ,5 ]
Tang, Mingliang [6 ,7 ]
Cao, Wei [8 ]
Xiang, Shang [9 ]
Zhang, Chen [10 ]
Yang, Jianming [8 ]
Gao, Xia [4 ,5 ]
Ying, Zheng [2 ,3 ]
Chai, Renjie [1 ,10 ,11 ,12 ,13 ]
机构
[1] Southeast Univ, Jiangsu Prov HighTech Key Lab BioMed Res, Adv Inst Life & Hlth,Zhongda Hosp,Sch Life Sci &, State Key Lab Bioelectron,Dept Otolaryngol Head &, Nanjing 210096, Jiangsu, Peoples R China
[2] Soochow Univ, Jiangsu Key Lab Neuropsychiat Dis, Suzhou 215123, Jiangsu, Peoples R China
[3] Soochow Univ, Coll Pharmaceut Sci, Suzhou, Jiangsu, Peoples R China
[4] Nanjing Univ Med Sch, Affiliated Drum Tower Hosp, Dept Otolaryngol Head & Neck Surg, Jiangsu Prov Key Med Discipline Lab, 321 Zhongshan Rd, Nanjing 210008, Jiangsu, Peoples R China
[5] Res Inst Otolaryngol, Nanjing, Jiangsu, Peoples R China
[6] Soochow Univ, Affiliated Hosp 1, Inst Cardiovasc Sci, Coll Med, Suzhou, Jiangsu, Peoples R China
[7] Soochow Univ, Affiliated Hosp 1, Coll Med, Dept Cardiovasc Surg, Suzhou, Jiangsu, Peoples R China
[8] Anhui Med Univ, Dept Otolaryngol Head & Neck Surg, Affiliated Hosp 2, Hefei, Anhui, Peoples R China
[9] Nanjing Normal Univ, High Sch Affiliated, Nanjing, Jiangsu, Peoples R China
[10] Capital Med Univ, Beijing Key Lab Neural Regenerat & Repair, Beijing, Peoples R China
[11] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Dept Otolaryngol Head & Neck Surg, Chengdu, Sichuan, Peoples R China
[12] Nantong Univ, Co Innovat Ctr Neuroregenerat, Nantong, Jiangsu, Peoples R China
[13] Chinese Acad Sci, Inst Stem Cell & Regenerat, Beijing, Peoples R China
基金
美国国家科学基金会; 中国国家自然科学基金; 中国博士后科学基金; 国家重点研发计划;
关键词
ATF3; cell apoptosis; hair cells; kinetin; mitophagy; neomycin; PRKN-PINK1; FLUORESCENT PROTEIN; PARKIN; PINK1; AUTOPHAGY; MITOCHONDRIA; PROMOTES; E3; PARK2/PARKIN; RECRUITMENT; UBIQUITIN;
D O I
10.1080/15548627.2022.2062872
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:75 / 91
页数:17
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