Homocysteine activates T cells by enhancing endoplasmic reticulum-mitochondria coupling and increasing mitochondrial respiration

Abstract

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.

Homocysteine causes vascular endothelial dysfunction by disrupting endoplasmic reticulum redox homeostasis

“…Ero1α inhibits SERCA Ca 2+ pump activity [51] and stimulates IP 3 R-dependent Ca 2+ flux to the cytosol and mitochondria [52] , [53] . Ca 2+ flux across the ER-mitochondria contact sites stimulates mitochondrial outer membrane permeabilization and respiratory chain dysfunction, leading to an increase in ROS, which further enhances Ca 2+ release and causes fatal UPR and apoptosis [54] , [55] . Indeed, mice lacking ERO1α are partially protected against progressive heart failure in a transaortic constriction model [56] .…”

Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets

“…Mechanistically, homocysteine increased ER–mitochondria coupling, and uncoupling ER from mitochondria with the microtubule inhibitor nocodazole attenuated homocysteine‐stimulated mitochondrial reprogramming, IFN‐γ secretion and proliferation in T‐cells. These results suggest that juxtaposition of the ER and mitochondria is required for homocysteine‐promoted mitochondrial function and T‐cell activation in vitro (Feng et al ., ). Furthermore, as previously described, the inhibition of oxidative stress or ROS production relieves ER stress, which suggests homocysteine‐induced ROS production mediates ER stress (Kil et al ., ).…”

Hyperhomocysteinemia and Endothelial Dysfunction in Multiple Sclerosis

“…The effect of homocysteine on CD4 + -T-cells subsets was shown. According to Feng et al, homocysteine may induce Th1-cell proliferation and IFN-γ production [ 74 ]. The effect of homocysteine on Th17-cell differentiation and function also was shown [ 75 , 76 ].…”