Autophagy protects auditory hair cells against neomycin-induced damage.
Autophagy protects auditory hair cells against neomycin-induced damage.
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自噬保护听毛细胞免受新霉素引起的损伤
DOI：
10.1080/15548627.2017.1359449
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发表时间：
2017
期刊：
影响因子：
13.3
通讯作者：
Chai R
中科院分区：
文献类型：
--
作者：
He Z;Guo L;Shu Y;Fang Q;Zhou H;Liu Y;Liu D;Lu L;Zhang X;Ding X;Liu D;Tang M;Kong W;Sha S;Li H;Gao X;Chai R
氨基糖苷类抗生素对感觉毛细胞具有毒性。自噬（Macroautophagy/autophagy）是一种重要的、高度保守的自我消化途径，在维持细胞功能和应激下的生存能力方面发挥重要作用。然而，自噬在氨基糖苷类药物诱导的HC损伤中的作用尚不清楚。在这里，我们首次发现，自噬活性显着增加，包括增强的自噬体-溶酶体融合，在耳蜗毛细胞和HEI-OC-1细胞后，新霉素或庆大霉素损伤，这表明自噬可能与氨基糖苷类诱导的细胞死亡。然后，我们使用雷帕霉素，一种自噬激活剂，以增加自噬活性，并发现ROS水平，细胞凋亡和细胞死亡后，新霉素或庆大霉素损伤显着下降。相比之下，用自噬抑制剂3-甲基腺嘌呤（3-MA）或自噬相关（ATG）蛋白的敲低治疗导致自噬活性降低，ROS水平显著增加，细胞凋亡和新霉素或庆大霉素损伤后的细胞死亡。最后，在新霉素损伤后，抗氧化剂N-乙酰半胱氨酸可以成功地防止由3-MA处理或ATG敲低诱导的细胞凋亡和HC损失的增加，这表明自噬通过抑制氧化应激来保护新霉素诱导的HC损伤。我们还发现，在新霉素处理后，HEI-OC-1细胞中的选择性自噬（线粒体自噬）并没有消除功能障碍的线粒体，这表明自噬可能不会直接靶向受损的线粒体进行降解。本研究表明，适度的ROS水平可以促进自噬以回收受损的细胞成分并维持细胞内稳态，而自噬的诱导可以通过抑制氨基糖苷类损伤后ROS的积累来抑制细胞凋亡并保护HC。
ABSTRACT 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.
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影响因子：
19
作者：
Feng, Yuchen;Yao, Zhiyuan;Klionsky, Daniel J.
通讯作者：
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影响因子：
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影响因子：
6.1
作者：
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通讯作者：
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影响因子：
1.6
作者：
Kalinec, GM;Webster, P;Kalinec, F
通讯作者：
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