Downregulation of SIRT3 Aggravates Lung Ischemia Reperfusion Injury by Increasing Mitochondrial Fission and Oxidative Stress through HIF-1α-Dependent Mechanisms

Abstract

Lung ischemia-reperfusion injury (LIRI) is a severe multifaceted pathological condition that can lead to poor patient outcome where oxidative stress and the resulting inflammatory response can trigger and exacerbate tissue damage in LIRI patients. Sirtuin3 (SIRT3), a member of the sirtuin family, protects against oxidative stress-related diseases. However, it remains unclear if and how SIRT3 alleviates lung injury induced by ischemia/reperfusion (I/R). Our previous study showed that lung tissue structures were severely damaged at 6 h after lung I/R in mice, however, repair of the injured lung tissue was significant at 24 h. In this study, we found that both SIRT3 mRNA and protein levels were markedly increased at 24 h after lung I/R in vivo. Meanwhile, inhibition of SIRT3 aggravated lung injury and inflammation, augmented mitochondrial fission and oxidative stress and increased Hypoxia-inducible factor-1α (HIF-1α) expression in vivo. The results suggest that SIRT3 may be an upstream regulator of HIF-1α expression. Knockdown of SIRT3 resulted in excessive mitochondrial fission and increased oxidative stress in vitro, and we found that knocking down the expression of HIF-1α alleviated these changes. This suggests that the SIRT3-HIF-1α signaling pathway is involved in regulating mitochondrial function and oxidative stress. Furthermore, inhibition of dynamin-related protein 1 (Drp-1) by the inhibitor of mitophagy, Mdivi-1, blocked mitochondrial fission and alleviated oxidative stress in vitro. Taken together, our results demonstrated that downregulation of SIRT3 aggravates LIRI by increasing mitochondrial fission and oxidative stress. Activation of SIRT3 inhibits mitochondrial fission and this mechanism may serve as a new therapeutic strategy to treat LIRI.

The neuroprotective effects of SFGDI on sirtuin 3-related oxidative stress by regulating the Sirt3/SOD/ROS pathway and energy metabolism in BV2 cells

“…27 Furthermore, the decrease in Sirt3 levels plays a crucial role in energy metabolism processes, exacerbating oxidative stress damage, disrupting the intracellular GSH homeostasis, and impeding the GSH-Px activity. [28][29][30] The decline in SOD and GSH-Px activities was closely associated with an elevated level of ROS, as evidenced by the results of ROS level assessment presented in Fig. 5E and F. 31 Compared to the control group, the model group showed a significant rise in the fluorescence intensity of the ROS probe.…”

GSDMD promotes neutrophil extracellular traps via mtDNA-cGAS-STING pathway during lung ischemia/reperfusion

“…Mice in the DSF + I/R group were given intraperitoneal injections of disulfiram (50 mg/kg) (PHR1690, Sigma-Aldrich, St. Louis, USA) at 24 h and 4 h prior to the surgery. The LIRI model was established as previously described [ 36 ]. Mice were anesthetized with an intraperitoneal injection of pentobarbital (50 mg/kg).…”

“…The neutrophils were cultured in RPMI 1640 medium supplement with 10% FBS at 37 °C and 5% CO 2 . A H/R model in vitro was established using neutrophils as described previously [ 36 ]. Briefly, neutrophils were cultured in glucose- and serum-free medium and equilibrated with 1% O 2 , 94% N 2 , and 5% CO 2 for 2 h. For reoxygenation, Hypoxia-treated cells were incubated with glucose-containing medium at 37 °C in a 5% CO 2 atmospheric air for 6 h. For drug treatments, DSF (30 μM) or the STING inhibitor H-151(5 μM, HY-112693, MedChemExpress, NJ, USA) were administered to the neutrophils 1 hour prior to hypoxia exposure.…”