Mitochondrial immunometabolism in sepsis: orchestrating macrophage polarization and dysfunction

Sepsis is a life-threatening condition marked by dysregulated immune responses and organ dysfunction, with macrophages playing central roles in both hyperinflammation and immunosuppression. Recent advances highlight mitochondrial metabolism as a key regulator of macrophage polarization and function. Pro-inflammatory M1 macrophages rely on glycolysis and produce high levels of reactive oxygen species (ROS) and cytokines, while reparative M2 macrophages depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Mitochondrial dysfunction-characterized by excessive mitochondrial ROS (mtROS), impaired mitophagy, and disrupted fission/fusion dynamics-exacerbates immune dysregulation and tissue injury. Organ-specific macrophage metabolic reprogramming further influences sepsis pathology, particularly in the kidney, lung, and heart. Therapeutic strategies targeting mitochondrial pathways-such as small-molecule modulators, stem cell-derived extracellular vesicles, and RNA-based gene therapies-have shown promise in restoring macrophage homeostasis and improving outcomes. This review underscores the importance of immunometabolic regulation in sepsis and advocates for mitochondria-targeted interventions as a novel precision approach to immune modulation.