Sepsis-associated organ dysfunction plays a critical role in its high mortality, mainly in connection with
mitochondrial dysfunction. Whether the inhibition of mitochondrial fission is beneficial to
sepsis-related organ dysfunction and underlying mechanisms are unknown. Cecal
ligation and
puncture induced
sepsis in rats and dynamic related
protein 1 knockout mice,
lipopolysaccharide-treated vascular smooth muscle cells and cardiomyocytes, were used to explore the effects of inhibition of mitochondrial fission and specific mechanisms. Our study showed that mitochondrial fission inhibitor
Mdivi-1 could antagonize
sepsis-induced organ dysfunction including heart, vascular smooth muscle, liver, kidney, and intestinal functions, and prolonged animal survival. The further study showed that mitochondrial functions such as mitochondrial membrane potential,
adenosine-triphosphate contents,
reactive oxygen species,
superoxide dismutase and
malonaldehyde were recovered after
Mdivi-1 administration via improving mitochondrial morphology. And
sepsis-induced
inflammation and apoptosis in heart and vascular smooth muscle were alleviated through inhibition of mitochondrial fission and mitochondrial function improvement. The parameter trends in
lipopolysaccharide-stimulated cardiomyocytes and vascular smooth muscle cells were similar in vivo. Dynamic related
protein 1 knockout preserved
sepsis-induced organ dysfunction, and the animal survival was prolonged. Taken together, this finding provides a novel effective candidate
therapy for
severe sepsis/
septic shock and other critical clinical diseases.