Citrate synthase improves sepsis-induced lung injury by reconstructing the mitochondrial tricarboxylic acid cycle of macrophages

Abstract Background The destruction of mitochondrial function during sepsis-induced acute lung injury (sepsis-ALI) can lead to tissue cell damage and organ dysfunction. Citrate synthase (CS) may maintain cellular energy metabolism by enhancing the mitochondrial tricarboxylic acid cycle (TCA cycle) in macrophages. Methods 76 healthy donors and 89 sepsis patients were included. The levels of CS were determined using ELISA. We established a cecal ligation and puncture (CLP) model of sepsis to evaluate the effects of CS on lung injury by lung macrophages-specific CS knockdown or CS inhibitors. Isolated mouse lung macrophages were stimulated with LPS to observe the impact of CS overexpression and knockdown on TCA cycle. Results In sepsis patients, CS was expressed at low levels and positively correlates with lung function parameters. In sepsis mice, knockdown CS or inhibiting its expression exacerbated lung injury and oxidative stress. In macrophages, inhibiting CS expression affected TCA cycle and worsened cell apoptosis, while overexpressing CS promoted TCA cycle, alleviating cell apoptosis, enhancing cellular energy production, and reducing oxidative stress levels. The supplementation of citric acid (a downstream metabolite of CS) helped alleviate mitochondrial damage and promotes the TCA cycle. Conclusions These results suggest that targeting CS may be a promising therapeutic approach for treating sepsis.