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.

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.…”

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.…”