Mitochondrial dysfunction in sepsis-induced immunoparalysis: from immune-cell metabolic reprogramming to clinical biomarkers

Sepsis-induced immunoparalysis is a dynamic state of acquired immune dysfunction characterized by impaired antigen presentation, lymphocyte exhaustion, defective innate immune responses, and increased susceptibility to secondary infection. Increasing evidence suggests that mitochondrial dysfunction is a key metabolic mechanism underlying this immune failure. Rather than acting as a uniform injury signal, mitochondrial abnormalities affect immune-cell subsets in distinct ways: monocytes and macrophages lose antigen-presenting capacity, neutrophils develop impaired migration and antimicrobial activity, T cells acquire exhaustion-like phenotypes, and NK and B-cell responses become functionally constrained. This review summarizes how core mitochondrial processes, including bioenergetic failure, redox imbalance, mitochondrial danger-signal release, and defective quality control, contribute to sepsis-induced immunoparalysis. We further discuss how mitochondria-related readouts may complement established immune markers such as monocyte HLA-DR, lymphocyte count, PD-1/PD-L1, CD86, and IL-10 for patient stratification. Finally, we highlight therapeutic opportunities aimed at restoring mitochondrial fitness and immune competence in biomarker-defined septic patients.