SIRT3 Deficiency Promotes Lung Endothelial Pyroptosis Through Impairing Mitophagy to Activate NLRP3 Inflammasome During Sepsis-Induced Acute Lung Injury.

Abstract

Acute lung injury (ALI) is a major cause of death in bacterial sepsis due to endothelial inflammation and endothelial permeability defects. Mitochondrial dysfunction is recognized as a key mediator in the pathogenesis of sepsis-induced ALI. Sirtuin 3 (SIRT3) is a histone protein deacetylase involved in preservation of mitochondrial function, which has been demonstrated in our previous study. Here, we investigated the effects of SIRT3 deficiency on impaired mitophagy to promote lung endothelial cells (ECs) pyroptosis during sepsis-induced ALI. We found that 3-TYP aggravated sepsis-induced ALI with increased lung ECs pyroptosis and enhanced NLRP3 activation. Mitochondrial reactive oxygen species (mtROS) and extracellular mitochondrial DNA (mtDNA) released from damaged mitochondria could be exacerbated in SIRT3 deficiency, which further elicit NLRP3 inflammasome activation in lung ECs during sepsis-induced ALI. Furthermore, Knockdown of SIRT3 contributed to impaired mitophagy via downregulating Parkin, which resulted in mitochondrial dysfunction. Moreover, pharmacological inhibition NLRP3 or restoration of SIRT3 attenuates sepsis-induced ALI and sepsis severity in vivo. Taken together, our results demonstrated SIRT3 deficiency facilitated mtROS production and cytosolic release of mtDNA by impaired Parkin-dependent mitophagy, promoting to lung ECs pyroptosis through the NLRP3 inflammasome activation, which providing potential therapeutic targets for sepsis-induced ALI.