MPC1 regulates endotoxin tolerance of macrophages through mitochondrial oxidative stress resistance

Abstract

Increasing evidence highlights the crucial role of endotoxin tolerance in the regulation of the sepsis, yet its underlying mechanisms remain poorly understood. Here, we provide evidence to support a novel role for the mitochondrial pyruvate carrier1 (MPC1)-mediated mitochondrial oxidative stress resistance in regulation of endotoxin tolerance in macrophages. We observed a decrease in MPC1 expression in both in vitro and in vivo sepsis models, while LPS-tolerant macrophages exhibited increased MPC1 levels. Overexpression of MPC1 significantly reduced LPS-induced inflammatory responses and oxidative stress, suggesting its anti-inflammatory properties. Intriguingly, we found that overexpression of MPC1 did not foster endotoxin tolerance in macrophages. Furthermore, we found that overexpression of MPC1 inhibited mitochondrial oxidative stress resistance mediated by mitochondrial reactive oxygen species (mtROS), which weakened the resistance of macrophages to LPS secondary stimulation, and then inhibited endotoxin tolerance. Despite mtROS typically acting as pro-inflammatory mediators, our findings indicate that mtROS production, regulated via the SIRT3/SOD2 pathway, is essential for MPC1's control over mitochondrial oxidative stress resistance and endotoxin tolerance. Collectively, these findings uncover novel mechanisms through which MPC1 modulates inflammation and induces endotoxin tolerance, underscoring the potential of targeting MPC1 in sepsis treatment.