Mitochondrial-targeted ubiquinone alleviates concanavalin A-induced hepatitis via immune modulation.

Despite knowledge regarding the effects of antioxidants in ameliorating oxidative damage, evidence concerning their effects on activated immune cells is lacking. Here, a concanavalin A (Con A)-induced hepatitis mouse model was used to investigate the protective effects and immune regulatory mechanisms of mitochondrial-targeted ubiquinone (MitoQ).

Wild-type (WT) and CD1d-knockout (CD1d^-/-, NKT cell deficient) mice were pretreated with MitoQ and then intravenously injected with a sublethal dose of Con A. Serum transaminase and inflammatory cytokine levels were tested. Immune cell functions and AMPK/mTORC1 pathway activation in liver tissue were also evaluated.

NKT cells were critical for extensive pro-inflammatory cytokine production and prolonged liver injury upon Con A challenge, while IFN-γ-producing non-NKT cells played an important role during the hyperacute phase. MitoQ treatment not only ameliorated NKT cell-independent hyperacute hepatitis within 12 h post Con A administration but also alleviated NKT cell-dependent extended liver injury at 24 h. The underlying mechanisms involved an inhibition of the heightened activation of iNKT cells and conventional T cells, suppression of the excessive production of IFN-γ, TNF-α and IL-6, and modulation of aberrant AMPK and mTORC1 pathways.MitoQ efficiently alleviates Con A-induced hepatitis through immune regulation, suggesting a new therapeutic approach for immune-mediated liver injury by targeting mitochondrial ROS.