摘要
Hyperhomocysteinemia （HHcy） accelerates atherosclero- sis by increasing proliferation and stimulating cytokine secretion in Tcells. 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 activa- tion in mice was accompanied by increased levels of mitochondrial reactive oxygen species （ROS） and calcium, mitochondrial mass and respiration. Inhibiting mitochon- drial ROS production and calcium signals or blocking mitochondrial respiration largely blunted Hcy-induced T-cell interferon y （IFN-v） 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 uncou- pling ER-mitochondria by the microtubule inhibitor nocodazole attenuated Hcy-stimulated mitochondrial reprogramming, IFN-y secretion and proliferation in T cells, suggesting that juxtaposition of ER and mitochon-dria 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.
Hyperhomocysteinemia （HHcy） accelerates atherosclero- sis by increasing proliferation and stimulating cytokine secretion in Tcells. 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 activa- tion in mice was accompanied by increased levels of mitochondrial reactive oxygen species （ROS） and calcium, mitochondrial mass and respiration. Inhibiting mitochon- drial ROS production and calcium signals or blocking mitochondrial respiration largely blunted Hcy-induced T-cell interferon y （IFN-v） 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 uncou- pling ER-mitochondria by the microtubule inhibitor nocodazole attenuated Hcy-stimulated mitochondrial reprogramming, IFN-y secretion and proliferation in T cells, suggesting that juxtaposition of ER and mitochon-dria 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.
