Mitochondria-Macrophage Interactions in Sepsis at Different Immune Stages: Integrating Immunometabolic Reprogramming, Organ Damage, and Therapeutic Strategies

Abstract: Sepsis is a life-threatening disorder caused by dysregulated host responses to infection, characterized by immune dysfunction, metabolic reprogramming, and multi-organ injury. Mitochondria, beyond their role in energy metabolism, act as central signaling hubs that integrate cellular metabolism, innate immunity, and inflammatory responses. Emerging evidence suggests that disrupted mitochondria–macrophage crosstalk forms a self-amplifying loop that drives excessive inflammation and organ dysfunction during sepsis. This review highlights recent advances in understanding how mitochondrial quality control and immunometabolic remodeling regulate macrophage activation and function. We discuss the impact of key metabolic pathways, including glycolysis, oxidative phosphorylation, tricarboxylic acid cycle remodeling, and fatty acid metabolism, on macrophage polarization, as well as the dynamic roles of mitophagy, mitochondrial biogenesis, and mitochondrial dynamics throughout sepsis progression. We further summarize current challenges and potential therapeutic strategies targeting the mitochondria–macrophage axis. Elucidating this regulatory network may provide new insights into precision medicine and the development of targeted therapies for sepsis. Keywords: sepsis, mitochondria, macrophages, mitochondrial quality control, metabolic reprogramming, multiple organ dysfunction