SIRT3
SOD2
自噬
褪黑素
生物
线粒体
超氧化物歧化酶
活性氧
细胞生物学
程序性细胞死亡
锡尔图因
细胞凋亡
乙酰化
生物化学
氧化应激
内分泌学
基因
作者
Huifeng Pi,Shangcheng Xu,Russel J. Reíter,Pengyi Guo,Lei Zhang,Yuming Li,Min Li,Zhenwang Cao,Li Tian,Jia Xie,Ruiqi Zhang,Mindi He,Yonghui Lu,Chuan Liu,Weixia Duan,Zhengping Yu,Zhou Zhou
出处
期刊:Autophagy
[Informa]
日期:2015-07-03
卷期号:11 (7): 1037-1051
被引量:271
标识
DOI:10.1080/15548627.2015.1052208
摘要
Cadmium is one of the most toxic metal compounds found in the environment. It is well established that Cd induces hepatotoxicity in humans and multiple animal models. Melatonin, a major secretory product of the pineal gland, has been reported to protect against Cd-induced hepatotoxicity. However, the mechanism behind this protection remains to be elucidated. We exposed HepG2 cells to different concentrations of cadmium chloride (2.5, 5, and 10 μM) for 12 h. We found that Cd induced mitochondrial-derived superoxide anion-dependent autophagic cell death. Specifically, Cd decreased SIRT3 protein expression and activity and promoted the acetylation of SOD2, superoxide dismutase 2, mitochondrial, thus decreasing its activity, a key enzyme involved in mitochondrial ROS production, although Cd did not disrupt the interaction between SIRT3 and SOD2. These effects were ameliorated by overexpression of SIRT3. However, a catalytic mutant of SIRT3 (SIRT3(H248Y)) lacking deacetylase activity lost the capacity to suppress Cd-induced autophagy. Notably, melatonin treatment enhanced the activity but not the expression of SIRT3, decreased the acetylation of SOD2, inhibited mitochondrial-derived O2(•-) production and suppressed the autophagy induced by 10 μM Cd. Moreover, 3-(1H-1,2,3-triazol-4-yl)pyridine, a confirmed selective SIRT3 inhibitor, blocked the melatonin-mediated suppression of autophagy by inhibiting SIRT3-SOD2 signaling. Importantly, melatonin suppressed Cd-induced autophagic cell death by enhancing SIRT3 activity in vivo. These results suggest that melatonin exerts a hepatoprotective effect on mitochondrial-derived O2(•-)-stimulated autophagic cell death that is dependent on the SIRT3/SOD2 pathway.
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