SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin.
SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin.
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DOI：
10.1080/15548627.2015.1052208
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发表时间：
2015
期刊：
影响因子：
13.3
通讯作者：
Zhou Z
中科院分区：
文献类型：
--
作者：
Pi H;Xu S;Reiter RJ;Guo P;Zhang L;Li Y;Li M;Cao Z;Tian L;Xie J;Zhang R;He M;Lu Y;Liu C;Duan W;Yu Z;Zhou Z
镉是环境中毒性最大的金属化合物之一。已确定镉在人类和多种动物模型中诱导肝毒性。褪黑激素是松果体的主要分泌物，有研究表明其对镉诱导的肝毒性有保护作用。然而，这种保护背后的机制仍有待阐明。我们将HepG 2细胞暴露于不同浓度的氯化镉（2.5、5和10 μM）中12 h。我们发现，镉诱导大鼠源性超氧阴离子依赖性自噬细胞死亡。具体而言，镉降低SIRT 3蛋白的表达和活性，并促进SOD 2，超氧化物歧化酶2，线粒体的乙酰化，从而降低其活性，参与线粒体ROS产生的关键酶，虽然镉没有破坏SIRT 3和SOD 2之间的相互作用。这些作用通过SIRT 3的过表达而改善。然而，缺乏脱乙酰酶活性的SIRT 3催化突变体（SIRT 3 H248 Y）失去了抑制Cd诱导的自噬的能力。值得注意的是，褪黑激素处理增强了SIRT 3的活性，但没有表达，降低了SOD 2的乙酰化，抑制了脑源性O2·−的产生，并抑制了10 μM Cd诱导的自噬。此外，3-（1H-1，2，3-三唑-4-基）吡啶，一种已证实的选择性SIRT 3抑制剂，通过抑制SIRT 3-SOD 2信号传导阻断褪黑激素介导的自噬抑制。重要的是，褪黑激素抑制镉诱导的自噬性细胞死亡，通过增强SIRT 3的活性在体内。这些结果表明，褪黑激素对肝脏来源的O2·−刺激的自噬细胞死亡具有肝保护作用，这依赖于SIRT 3/SOD 2途径。
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 (SIRT3H248Y) 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.