Protective Effects of Inhibition of Mitochondrial Fission on Organ Function After Sepsis

Abstract

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.

The Four Key Genes Participated in and Maintained Atrial Fibrillation Process via Reprogramming Lipid Metabolism in AF Patients

“…The sodium pentobarbital (45 mg/kg, i. p.) was used for anesthetizing rats for the surgical procedure. The cecal ligation and puncture (CLP) was applied to reproduce systemic inflammatory response as described previously ( Zhu et al, 2021 ). Briefly, the cecum was exposed carefully and ligated and punctured 0.7 cm from a distance with a triangular needle 1.5 mm in diameter, and fecal matter was allowed to flow into the abdominal cavity freely.…”

Secretory Factors from Calcium-Sensing Receptor-Activated SW872 Pre-Adipocytes Induce Cellular Senescence and A Mitochondrial Fragmentation-Mediated Inflammatory Response in HepG2 Cells

“…Furthermore, in a rat model of ischemia, Mdivi-1 increased Δψ and the authors attribute this behavior to the regulatory action of the reagent on mitophagy mediated by PINK/Parking proteins [ 56 ]. It was also shown in LPS-exposed cardiomyocytes that Mdivi-1 contributes to the recovery of Δψ [ 57 ]. The effects of Mdivi-1 on the Δψ regulation would be related to mitochondrial membrane integrity maintenance.…”

Effects of Mdivi‐1 on Extending the Golden Treatment Time following Hemorrhagic Shock in Hot Environment in Rats

“…[16][17][18] Our previous study found that inhibition of mitochondrial fission could decrease the mortality of sepsis, protect vital organ functions, including cardiovascular function, liver, kidney, and intestinal function. [14] Moreover, inhibition of mitochondrial over-fission could enhance tissue perfusion, oxygen supply and oxygen consumption. Present study demonstrated that inhibition of mitochondrial over-fission was beneficial to early treatment of hemorrhagic shock in hot environment that could prolong golden treatment time and protect organ function.…”

“…The studies confirmed that Mdivi-1 could protect the functions of heart, nerves and other organs by inhibiting mitochondrial division. [12][13][14] Whether Mdivi-1 is suitable for the early treatment of hemorrhagic shock in hot environment by inhibiting mitochondrial division is not known.…”