SVCT2-mediated ascorbic acid uptake buffers stress responses via DNA hydroxymethylation reprogramming of S100 calcium-binding protein A4 gene.
SVCT2-mediated ascorbic acid uptake buffers stress responses via DNA hydroxymethylation reprogramming of S100 calcium-binding protein A4 gene.
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DOI：
10.1016/j.redox.2022.102543
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发表时间：
2022-12
期刊：
影响因子：
11.4
通讯作者：
Wang, Fang
中科院分区：
文献类型：
--
作者：
Han, Qian-Qian;Wu, Peng-Fei;Li, Yi-Heng;Cao, Yu;Chen, Jian-Guo;Wang, Fang
关键词：
Vitamin C, a key antioxidant in the central nervous system, cycles between ascorbic acid and dehydroascorbic acid under pathophysiological conditions. Clinical evidence supports that the absence of vitamin C may be linked to depressive symptoms, but much less is known about the mechanism. Herein, we show that chronic stress disrupts the expression of ascorbic acid transporter, sodium-dependent vitamin C transport 2, and induces a deficiency in endogenous ascorbic acid in the medial prefrontal cortex, leading to depressive-like behaviors by disturbing redox-dependent DNA methylation reprogramming. Attractively, ascorbic acid (100 mg/kg-1000 mg/kg, intraperitoneal injection, as bioequivalent of an intravenous drip dose of 0.48 g–4.8 g ascorbic acid per day in humans) produces rapid-acting antidepressant effects via triggering DNA demethylation catalyzed by ten-eleven translocation dioxygenases. In particular, the mechanistic studies by both transcriptome sequencing and methylation sequencing have shown that S100 calcium binding protein A4, a potentially protective factor against oxidative stress and brain injury, mediates the antidepressant activity of ascorbic acid via activating erb-b2 receptor tyrosine kinase 4 (ErbB4)-brain derived neurotrophic factor (BDNF) signaling pathway. Overall, our findings reveal a novel nutritional mechanism that couples stress to aberrant DNA methylation underlying depressive-like behaviors. Therefore, application of vitamin C may be a potential strategy for the treatment of depression. Chronic stress disturbs ascorbic acid homeostasis in the mPFC. SVCT2-dependent ascorbic acid uptake in the mPFC buffers stress response. Ascorbic acid produces rapid-acting antidepressant effects via TET-dependent DNA oxidation. S100A4-ErbB4-BDNF signaling pathway is involved in the antidepressant effects of ascorbic acid.
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影响因子：
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作者：
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DOI：
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