Autophagy protects auditory hair cells against neomycin-induced damage

被引:218
作者
He, Zuhong [1 ,2 ]
Guo, Lingna [1 ,3 ]
Shu, Yilai [4 ,5 ]
Fang, Qiaojun [1 ,3 ]
Zhou, Han [6 ]
Liu, Yongze [6 ]
Liu, Dingding [6 ]
Lu, Ling [6 ]
Zhang, Xiaoli [6 ]
Ding, Xiaoqiong [7 ]
Liu, Dong [3 ]
Tang, Mingliang [1 ,3 ]
Kong, Weijia [2 ]
Sha, Suhua [8 ]
Li, Huawei [4 ,5 ]
Gao, Xia [6 ,9 ]
Chai, Renjie [1 ,3 ,9 ]
机构
[1] Southeast Univ, Inst Life Sci, Key Lab Dev Genes & Human Dis, Minist Educ, Nanjing, Jiangsu, Peoples R China
[2] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Otorhinolaryngol, Wuhan, Hubei, Peoples R China
[3] Nantong Univ, Coinnovat Ctr Neuroregenerat, Nantong, Peoples R China
[4] Fudan Univ, Hearing Res Inst, Affiliated Eye & ENT Hosp, Dept Otolaryngol, Shanghai, Peoples R China
[5] Natl Hlth & Family Planning Commiss, Key Lab Hearing Med, Shanghai, Peoples R China
[6] Nanjing Univ, Jiangsu Prov Key Med Discipline Lab, Dept Otolaryngol Head & Neck Surg, Affiliated Drum Tower Hosp,Med Sch, Nanjing, Jiangsu, Peoples R China
[7] Southeast Univ, Zhongda Hosp, Dept Otolaryngol Head & Neck Surg, Nanjing, Jiangsu, Peoples R China
[8] Med Univ South Carolina, Dept Pathol & Lab Med, Charleston, SC USA
[9] Res Inst Otolaryngol, Nanjing, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
aminoglycosides; apoptosis; autophagic flux; autophagosome; hair cell protection; lysosome; oxidative stress; OXIDATIVE STRESS; SIGNALING PATHWAYS; IN-VITRO; DEATH; APOPTOSIS; INCREASES; KINASE; REGENERATION; DEGRADATION; OTOTOXICITY;
D O I
10.1080/15548627.2017.1359449
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Aminoglycosides are toxic to sensory hair cells (HCs). Macroautophagy/autophagy is an essential and highly conserved self-digestion pathway that plays important roles in the maintenance of cellular function and viability under stress. However, the role of autophagy in aminoglycoside-induced HC injury is unknown. Here, we first found that autophagy activity was significantly increased, including enhanced autophagosome-lysosome fusion, in both cochlear HCs and HEI-OC-1 cells after neomycin or gentamicin injury, suggesting that autophagy might be correlated with aminoglycoside-induced cell death. We then used rapamycin, an autophagy activator, to increase the autophagy activity and found that the ROS levels, apoptosis, and cell death were significantly decreased after neomycin or gentamicin injury. In contrast, treatment with the autophagy inhibitor 3-methyladenine (3-MA) or knockdown of autophagy-related (ATG) proteins resulted in reduced autophagy activity and significantly increased ROS levels, apoptosis, and cell death after neomycin or gentamicin injury. Finally, after neomycin injury, the antioxidant N-acetylcysteine could successfully prevent the increased apoptosis and HC loss induced by 3-MA treatment or ATG knockdown, suggesting that autophagy protects against neomycin-induced HC damage by inhibiting oxidative stress. We also found that the dysfunctional mitochondria were not eliminated by selective autophagy (mitophagy) in HEI-OC-1 cells after neomycin treatment, suggesting that autophagy might not directly target the damaged mitochondria for degradation. This study demonstrates that moderate ROS levels can promote autophagy to recycle damaged cellular constituents and maintain cellular homeostasis, while the induction of autophagy can inhibit apoptosis and protect the HCs by suppressing ROS accumulation after aminoglycoside injury.
引用
收藏
页码:1884 / 1904
页数:21
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