Key result
Metformin reduces ROS accumulation ~31% and preserves cardiac function in septic rats.
Why the study?
The molecular mechanisms of sepsis-induced cardiomyopathy remain incompletely understood, hindering the development of targeted therapies.
Metformin protects against sepsis-induced cardiomyopathy in preclinical models by inhibiting reverse electron transfer at mitochondrial complex I, thereby reducing oxidative stress and inflammation.
Hypothesis-generating for metformin in sepsis cardiomyopathy; leaves open whether RET inhibition at complex I improves human outcomes.
Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication of sepsis; however, its molecular mechanisms remain incompletely understood, which has hindered the development of targeted therapies. We hypothesized that excessive mitochondrial reactive oxygen species (mtROS) production through reverse electron transfer (RET) at mitochondrial complex I contributes to septic myocardial injury and that metformin, a clinically used inhibitor of mitochondrial complex I, protects the myocardium by inhibiting this process. In lipopolysaccharide-stimulated H9C2 cardiomyocytes and cecal ligation and puncture-induced septic rats, sepsis was characterized by an elevated mitochondrial membrane potential, accompanied by succinate accumulation, an increased NADH/NAD+ ratio, and impaired downstream electron transport. These metabolic changes established favorable conditions for RET-mediated mtROS generation. Metformin inhibited complex I activity and selectively suppressed RET-mediated mtROS generation without increasing ROS production associated with forward electron transport (FET). This effect was accompanied by attenuated inflammatory responses and apoptosis. In septic rats, metformin preserved cardiac function and alleviated myocardial oxidative stress and injury. Overall, these results suggest that RET at mitochondrial complex I represents a potential therapeutic target in SICM and support the use of metformin as a promising strategy for preventing and treating septic myocardial dysfunction.
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He et al. (2026) studied Sepsis-induced cardiomyopathy (n=18). Metformin vs. Saline / untreated control was evaluated on Intracellular ROS levels (mean fluorescence intensity) (p=<0.001). Metformin significantly suppressed LPS-induced intracellular reactive oxygen species accumulation and preserved cardiac function in septic rats by inhibiting reverse electron transfer at mitochondrial complex I.
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