NOX2-derived hydrogen peroxide impedes the AMPK/Akt-mTOR signaling pathway contributing to cell death in neuronal cells.
NOX2-derived hydrogen peroxide impedes the AMPK/Akt-mTOR signaling pathway contributing to cell death in neuronal cells.
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NOX2 衍生的过氧化氢阻碍 AMPK/Akt-mTOR 信号通路，导致神经元细胞死亡
DOI：
10.1016/j.cellsig.2022.110330
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发表时间：
2022-06
影响因子：
4.8
通讯作者：
Chen, Long
中科院分区：
文献类型：
--
作者：
Zhang, Ruijie;Liu, Chunxiao;Yang, Liu;Ji, Tong;Zhang, Nana;Dong, Xiaoqing;Chen, Xin;Ma, Jing;Gao, Wei;Huang, Shile;Chen, Long
帕金森病（Parkinson 'sdisease，PD）是一种典型的神经退行性疾病，其发病机制与氧化应激密切相关。NADPH氧化酶2（NOX 2）参与过氧化氢（H2 O2）的生成。最近，我们报道了用H2 O2和PD毒素（包括6-羟基多巴胺（6-OHDA）、1-甲基-4-苯基吡啶-1-鎓（MPP+）和鱼藤酮）处理，通过抑制mTOR通路诱导神经元凋亡。在这里，我们表明，6-OHDA，MPP+或鱼藤酮治疗诱导H2 O2的产生，通过上调水平的NOX 2及其调节蛋白（p22 phox，p40 phox，p47 phox，p67 phox，和Rac 1），导致细胞凋亡的细胞死亡在PC 12细胞和原代神经元。用夹竹桃素或二苯基碘鎓抑制NOX 2，或敲低NOX 2，可有力地减弱PD毒素诱发的NOX 2和H2 O2，从而阻碍AMPK的激活、Akt/mTOR的抑制和神经元细胞凋亡的诱导。过氧化氢酶（一种H2 O2清除酶）预处理可阻断PD毒素对细胞中NOX 2依赖性H2 O2产生、AMPK/Akt/mTOR信号传导和凋亡的影响。类似的效果也被认为是在细胞预处理与Mito-TEMPO，一种选择性的超氧化物清除剂，这意味着线粒体H2 O2依赖的机制参与。进一步的研究表明，异位表达组成性激活的Akt或显性失活的AMPKα，或用化合物C抑制AMPK抑制PD毒素诱导的NOX 2及其调节蛋白的表达，以及随后的H2 O2产生和细胞凋亡。综上所述，这些结果表明，某些PD毒素可以通过引发NOX 2衍生的H2 O2产生来阻碍导致神经元凋亡的AMPK/Akt-mTOR信号通路。我们的研究结果表明，PD中的神经元损失可以通过调节NOX 2，AMPK/Akt-mTOR信号和/或应用抗氧化剂来改善氧化应激来预防。
Oxidative stress is closely related to the pathogenesis of Parkinson’s disease (PD), a typical neurodegenerative disease. NADPH oxidase 2 (NOX2) is involved in hydrogen peroxide (H2O2) generation. Recently, we have reported that treatment with H2O2 and PD toxins, including 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenylpyridin-1-ium (MPP+) and rotenone, induces neuronal apoptosis by inhibiting the mTOR pathway. Here, we show that treatment with 6-OHDA, MPP+ or rotenone induced H2O2 generation by upregulating the levels of NOX2 and its regulatory proteins (p22phox, p40phox, p47phox, p67phox, and Rac1), leading to apoptotic cell death in PC12 cells and primary neurons. Inhibition of NOX2 with apocynin or diphenyleneiodonium, or knockdown of NOX2 powerfully attenuated PD toxins-evoked NOX2 and H2O2, thereby hindering activation of AMPK, inhibition of Akt/mTOR, and induction of apoptosis in neuronal cells. Pretreatment with catalase, a H2O2-scavenging enzyme, blocked the effects of PD toxins on NOX2-dependent H2O2 production, AMPK/Akt/mTOR signaling and apoptosis in the cells. Similar effects were also seen in the cells pretreated with Mito-TEMPO, a mitochondria-selective superoxide scavenger, implying a mitochondrial H2O2-dependent mechanism involved. Further research revealed that ectopic expression of constitutively active Akt or dominant negative AMPKα, or inhibition of AMPK with compound C suppressed PD toxins-induced expression of NOX2 and its regulatory proteins, as well as consequential H2O2 production and apoptosis in the cells. Taken together, these results indicate that certain PD toxins can impede the AMPK/Akt-mTOR signaling pathway leading to neuronal apoptosis by eliciting NOX2-derived H2O2 production. Our findings suggest that neuronal loss in PD may be prevented by regulating the NOX2, AMPK/Akt-mTOR signaling and/or applying antioxidants to ameliorate oxidative stress.
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