Citrate synthases improve sepsis-induced lung injury by reconstructing the mitochondrial tricarboxylic acid cycle of macrophages.

Abstract

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