Crosstalk between Ca2+ signaling and mitochondrial H2O2 is required for rotenone inhibition of mTOR signaling pathway leading to neuronal apoptosis.
Crosstalk between Ca2+ signaling and mitochondrial H2O2 is required for rotenone inhibition of mTOR signaling pathway leading to neuronal apoptosis.
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Ca2 信号传导和线粒体 H2O2 之间的串扰是鱼藤酮抑制 mTOR 信号通路导致神经元凋亡所必需的
DOI：
10.18632/oncotarget.7183
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发表时间：
2016-02-16
期刊：
影响因子：
--
通讯作者：
Chen L
中科院分区：
文献类型：
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作者：
Liu C;Ye Y;Zhou Q;Zhang R;Zhang H;Liu W;Xu C;Liu L;Huang S;Chen L
鱼藤酮是一种神经毒性杀虫剂，可导致与帕金森病相关的多巴胺能神经元丧失。以往的研究表明鱼藤酮诱导神经细胞凋亡部分是通过触发过氧化氢（H2 O2）依赖性抑制mTOR通路。然而，其基本机制尚未完全了解。在这里，我们表明鱼藤酮升高细胞内游离钙离子（[Ca 2 +]i）水平，并激活CaMKII，导致抑制mTOR信号传导和诱导神经元凋亡。用BAPTA/AM螯合[Ca 2 +]i，用EGTA阻止细胞外Ca 2+内流，用KN 93抑制CaMK II，或沉默CaMK II显著减弱鱼藤酮诱导的H2 O2产生，mTOR抑制和细胞死亡。有趣的是，使用TTFA，抗霉素A，过氧化氢酶或Mito-TEMPO，我们发现鱼藤酮诱导的线粒体H2 O2也反过来升高[Ca 2 +]i水平，从而刺激CaMKII，导致mTOR通路的抑制和神经元凋亡的诱导。表达野生型mTOR或组成性激活的S6 K1或沉默4 E-BP 1增强了过氧化氢酶、Mito-TEMPO、BAPTA/AM或EGTA对鱼藤酮诱导的[Ca 2 +]i升高、CaMKII磷酸化和神经元凋亡的抑制作用。总之，结果表明，钙信号和线粒体H2 O2之间的串扰是鱼藤酮抑制mTOR介导的S6 K1和4 E-BP 1途径所必需的。因此，如何控制细胞内Ca ~（2+）的过度升高和线粒体H_2O_2的过度产生，可能是防治鱼藤酮神经毒性的一条新途径。
Rotenone, a neurotoxic pesticide, induces loss of dopaminergic neurons related to Parkinson's disease. Previous studies have shown that rotenone induces neuronal apoptosis partly by triggering hydrogen peroxide (H2O2)-dependent suppression of mTOR pathway. However, the underlying mechanism is not fully understood. Here, we show that rotenone elevates intracellular free calcium ion ([Ca2+]i) level, and activates CaMKII, resulting in inhibition of mTOR signaling and induction of neuronal apoptosis. Chelating [Ca2+]i with BAPTA/AM, preventing extracellular Ca2+ influx using EGTA, inhibiting CaMKII with KN93, or silencing CaMKII significantly attenuated rotenone-induced H2O2 production, mTOR inhibition, and cell death. Interestingly, using TTFA, antimycin A, catalase or Mito-TEMPO, we found that rotenone-induced mitochondrial H2O2 also in turn elevated [Ca2+]i level, thereby stimulating CaMKII, leading to inhibition of mTOR pathway and induction of neuronal apoptosis. Expression of wild type mTOR or constitutively active S6K1, or silencing 4E-BP1 strengthened the inhibitory effects of catalase, Mito-TEMPO, BAPTA/AM or EGTA on rotenone-induced [Ca2+]i elevation, CaMKII phosphorylation and neuronal apoptosis. Together, the results indicate that the crosstalk between Ca2+ signaling and mitochondrial H2O2 is required for rotenone inhibition of mTOR-mediated S6K1 and 4E-BP1 pathways. Our findings suggest that how to control over-elevation of intracellular Ca2+ and overproduction of mitochondrial H2O2 may be a new approach to deal with the neurotoxicity of rotenone.