Homocysteine activates T cells by enhancing endoplasmic reticulum-mitochondria coupling and increasing mitochondrial respiration.
Homocysteine activates T cells by enhancing endoplasmic reticulum-mitochondria coupling and increasing mitochondrial respiration.
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同型半胱氨酸通过增强内质网-线粒体偶联和增加线粒体呼吸来激活 T 细胞
DOI：
10.1007/s13238-016-0245-x
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发表时间：
2016-06
期刊：
影响因子：
21.1
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Feng J;Lü S;Ding Y;Zheng M;Wang X
高同型半胱氨酸血症（HHcy）通过增加T细胞增殖和刺激细胞因子分泌加速动脉粥样硬化。然而，同型半胱氨酸（Hcy）介导的T细胞活化是否与代谢重编程相关尚不清楚。在这里，我们的体内和体外研究表明，hcy刺激小鼠脾t细胞活化伴随着线粒体活性氧（ROS）和钙水平的增加，线粒体质量和呼吸增加。抑制线粒体ROS生成和钙信号或阻断线粒体呼吸在很大程度上减弱了hcy诱导的t细胞干扰素γ (IFN-γ)的分泌和增殖。Hcy还能增强T细胞内质网（ER）应激，4-苯基丁酸抑制内质网应激可阻断Hcy诱导的T细胞活化。在机制上，Hcy增加了ER-线粒体偶联，而微管抑制剂nocodazole解除ER-线粒体偶联则减弱了Hcy刺激的线粒体重编程、IFN-γ分泌和T细胞增殖，这表明Hcy促进线粒体功能和T细胞活化需要ER和线粒体的并立。总之，Hcy通过增加er -线粒体偶联和调节代谢重编程来促进t细胞活化。
Hyperhomocysteinemia (HHcy) accelerates atherosclerosis by increasing proliferation and stimulating cytokine secretion in T cells. However, whether homocysteine (Hcy)-mediated T cell activation is associated with metabolic reprogramming is unclear. Here, our in vivo and in vitro studies showed that Hcy-stimulated splenic T-cell activation in mice was accompanied by increased levels of mitochondrial reactive oxygen species (ROS) and calcium, mitochondrial mass and respiration. Inhibiting mitochondrial ROS production and calcium signals or blocking mitochondrial respiration largely blunted Hcy-induced T-cell interferon γ (IFN-γ) secretion and proliferation. Hcy also enhanced endoplasmic reticulum (ER) stress in T cells, and inhibition of ER stress with 4-phenylbutyric acid blocked Hcy-induced T-cell activation. Mechanistically, Hcy increased ER-mitochondria coupling, and uncoupling ER-mitochondria by the microtubule inhibitor nocodazole attenuated Hcy-stimulated mitochondrial reprogramming, IFN-γ secretion and proliferation in T cells, suggesting that juxtaposition of ER and mitochondria is required for Hcy-promoted mitochondrial function and T-cell activation. In conclusion, Hcy promotes T-cell activation by increasing ER-mitochondria coupling and regulating metabolic reprogramming.