Mitochondrial immunometabolism in sepsis: bridging immune cell dysfunction and organ failure

Sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, remains a leading cause of mortality in critical care, and sepsis-associated multiple organ failure continues to defy effective therapy. Increasing evidence positions mitochondria at the interface of cellular bioenergetics and innate immune signaling, making mitochondrial immunometabolism a compelling framework for understanding sepsis pathophysiology. In this mini-review, we synthesize how mitochondrial bioenergetic dysfunction shapes immune cell function across the dynamic course of sepsis, from the glycolytic, oxidative phosphorylation (OXPHOS)-uncoupled state of the hyperinflammatory phase to the bioenergetic failure of the immunoparalytic phase. We examine the contested roles of mitochondrial quality-control mechanisms: mitophagy, dynamics, and biogenesis, in immune cell remodeling, and propose that their net effect follows a time- and cell-type-dependent pattern rather than a fixed protective or deleterious role. We further discuss how mitochondrial damage-associated molecular patterns (mtDAMPs), mitochondrial DNA (mtDNA), reactive oxygen species (mtROS), and remodeled cardiolipin activate the cGAS-STING pathway and the NLRP3 inflammasome and cross-regulate one another to amplify inflammation and drive organ injury. Integrating these themes, we highlight mitochondrial immunometabolic crosstalk between key immune cell subsets (macrophages, neutrophils, and lymphocytes) and the parenchymal cells of vulnerable target organs (heart, kidney, lung, and the gut-liver axis). Finally, we identify knowledge gaps spanning temporal dynamics, cellular heterogeneity, and clinical translation, acknowledge the limitations of the current evidence, and outline emerging therapeutic and monitoring strategies. Collectively, mitochondrial immunometabolism links immune cell dysfunction to organ failure and may guide stage- and endotype-specific interventions in sepsis.