Mitochondrial Reverse Electron Transfer Contributes to Oxidative Damage in Sepsis-Induced Cardiomyopathy

Sepsis-induced cardiomyopathy (SICM) is a severe complication of sepsis characterized by myocardial depression and high mortality, yet the underlying mechanisms remain incompletely understood. Here, we provide evidence supporting reverse electron transfer (RET) at mitochondrial complex I as a contributing pathogenic mechanism linking metabolic disturbances to myocardial injury in SICM. Using LPS-stimulated H9C2 cardiomyocytes and cecal ligation and puncture (CLP)-induced septic rats, we integrated metabolomic profiling, mitochondrial functional analyses, and pharmacological interventions to investigate the role of RET in sepsis-induced cardiac dysfunction. We found that sepsis establishes a permissive metabolic environment for RET, characterized by elevated mitochondrial membrane potential (ΔΨm), NADH/NAD⁺ redox imbalance, and impaired downstream electron transport chain function. Enhanced RET is associated with excessive mitochondrial superoxide production, accompanied by oxidative stress, inflammation, and cardiomyocyte apoptosis. Notably, succinate accumulation provided the reducing equivalents necessary to fuel RET under these conditions. Pharmacological targeting of the RET pathway by inhibiting succinate dehydrogenase with dimethyl malonate (DMM) attenuated LPS-induced cellular injury and CLP-induced cardiac dysfunction, whereas supplementation with the succinate precursor dimethyl succinate (DMS) exacerbated these pathologies consistently with enhanced RET involvement. Collectively, our findings implicate RET at complex I as a significant contributing mechanism in SICM and highlight RET-targeted interventions as a promising therapeutic strategy for this devastating condition.