Downregulation of SIRT3 Aggravates Lung Ischemia Reperfusion Injury by Increasing Mitochondrial Fission and Oxidative Stress through HIF-1α-Dependent Mechanisms. (29th September 2022)

• Record Type: Journal Article
• Authors: Liu, Chunxia; Pei, Shenglin; Dai, Huijun; Liu, Zhen; Ye, Mengling; Liu, Hao; He, Xiaojing; Wu, Siyi; Qin, Yi; Lin, Fei
• Other Names: Garcia-Rivas Gerardo Academic Editor.
• Is Part Of: Oxidative medicine and cellular longevity. Volume 2022(2022)
• Publication Date: 2022-09-29
• Subjects: Oxidative stress -- Periodicals; Cells -- Aging -- Periodicals; Cells -- Aging; Oxidative stress; Oxidative Stress -- Periodicals; Cell Aging -- Periodicals; Periodicals; 611.0181
• DOI: 10.1155/2022/9041914
• Languages: English
• ISSNs: 1942-0900

Abstract

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.