The central role of mitochondrial pathology in sepsis-induced cardiomyopathy: from molecular mechanisms to clinical translation

Abstract

Sepsis-induced cardiomyopathy (SIC) affects approximately 50% of severe sepsis patients, with mortality rates approaching 80%. This review examines mitochondrial pathology as the central orchestrator of SIC progression. Mitochondrial dysfunction encompasses impaired oxidative phosphorylation (OXPHOS), causing bioenergetic failure; mitochondrial DNA (mtDNA) release activating cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes, Toll-like receptor 9, and NOD-like receptor family pyrin domain containing 3 pathways; ETC dysfunction generating explosive reactive oxygen species (ROS); defective mitophagy leading to damaged mitochondria accumulation; and disturbed mitochondrial dynamics with excessive fission and suppressed fusion. Intercellular mitochondrial transfer through tunneling nanotubes (TNTs) exhibits paradoxical dual effects. Mitochondria-targeted antioxidants selectively accumulate within mitochondria to scavenge ROS and preserve membrane potential. Nrf2 activators enhance endogenous antioxidant defenses. Melatonin modulates mitochondrial function through Ripk3 inhibition. Clinical translation faces substantial obstacles due to sepsis heterogeneity, animal model limitations, and disease complexity. This review integrates mitochondrial biology, immunometabolism, and translational medicine to identify promising directions for improving patient outcomes.