Vitamin C controls neuronal necroptosis under oxidative stress
Vitamin C controls neuronal necroptosis under oxidative stress
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DOI：
10.1016/j.redox.2019.101408
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发表时间：
2020-01-01
期刊：
影响因子：
11.4
通讯作者：
Nualart, Francisco
中科院分区：
文献类型：
--
作者：
Ferrada, Luciano;Barahona, Maria Jose;Nualart, Francisco
在生理条件下，维生素C是在中枢神经系统中发现的主要抗氧化剂，并以两种状态存在：还原为抗坏血酸（AA）和氧化为脱氢抗坏血酸（DHA）。然而，在病理生理条件下，AA被氧化为DHA。神经元中AA的氧化和随后DHA的产生与GSH浓度的降低、葡萄糖代谢的改变和神经元死亡相关。到目前为止，内源性分子作为内在的调节神经元坏死的氧化应激条件下是未知的。在这里，我们表明，AA治疗调节促凋亡和抗凋亡基因的表达。维生素C还调节RIPK 1/MLKL的表达，而神经元中AA的氧化诱导与坏死性凋亡和MLKL活化一致的形态学改变。在神经元中通过AA氧化激活坏死性凋亡导致气泡形成、膜完整性丧失和最终细胞爆炸。这些数据表明，坏死性凋亡是维生素C诱导的细胞死亡的靶点。
Under physiological conditions, vitamin C is the main antioxidant found in the central nervous system and is found in two states: reduced as ascorbic acid (AA) and oxidized as dehydroascorbic acid (DHA). However, under pathophysiological conditions, AA is oxidized to DHA. The oxidation of AA and subsequent production of DHA in neurons are associated with a decrease in GSH concentrations, alterations in glucose metabolism and neuronal death. To date, the endogenous molecules that act as intrinsic regulators of neuronal necroptosis under conditions of oxidative stress are unknown. Here, we show that treatment with AA regulates the expression of pro- and antiapoptotic genes. Vitamin C also regulates the expression of RIPK1/MLKL, whereas the oxidation of AA in neurons induces morphological alterations consistent with necroptosis and MLKL activation. The activation of necroptosis by AA oxidation in neurons results in bubble formation, loss of membrane integrity, and ultimately, cellular explosion. These data suggest that necroptosis is a target for cell death induced by vitamin C.