Downregulation of SIRT3 Aggravates Lung Ischemia Reperfusion Injury by Increasing Mitochondrial Fission and Oxidative Stress through HIF‐1<i>α</i>‐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‐1 α (HIF‐1 α ) expression in vivo . The results suggest that SIRT3 may be an upstream regulator of HIF‐1 α 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‐1 α alleviated these changes. This suggests that the SIRT3‐HIF‐1 α 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.

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