Targeting mitochondria: Unveiling novel therapeutic frontiers in sepsis.

Sepsis, a life-threatening condition characterized by organ dysfunction resulting from severe infection, has gained considerable attention for the involvement of mitochondrial (mt) dysfunction in disrupting cellular energy metabolism and exacerbating inflammatory injury through the release of mt components. During sepsis, damage to the mt electron transport chain (ETC) in various organs impairs the mitochondria's ability to sustain ATP production and effectively use oxygen. This dysfunction also increases mt membrane permeability, releasing mt damage-associated molecular patterns (DAMPs), i.e., proteins, phospholipids, metabolites, nucleic acids (NA), and reactive oxygen species (ROS). These DAMPs synergize with pathogen-associated molecular patterns (PAMPs) to amplify systemic inflammation and organ injury. Despite advances in understanding mt-driven metabolic and immune dysregulation, translating these insights into effective therapeutic interventions remains challenging. This review explores the dual role of mitochondria in sepsis, functioning both as central regulators of cellular metabolism and as key modulators of inflammatory responses. It evaluates mt-targeted therapeutic strategies, including metabolic reprogramming, induction of mt biogenesis, antioxidant approaches, and stabilization of mt membranes. Integrating findings from both preclinical and clinical studies highlights potential therapeutic avenues to alleviate sepsis-induced organ dysfunction and improve patient outcomes.