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Sirtuin3 (SIRT3), a member of the sirtuin family, protects against oxidative stress\u2010related 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\u2009h after lung I\/R in mice, however, repair of the injured lung tissue was significant at 24\u2009h. In this study, we found that both SIRT3 mRNA and protein levels were markedly increased at 24\u2009h after lung I\/R <jats:italic>in vivo<\/jats:italic>. Meanwhile, inhibition of SIRT3 aggravated lung injury and inflammation, augmented mitochondrial fission and oxidative stress and increased Hypoxia\u2010inducible factor\u20101<jats:italic>\u03b1<\/jats:italic> (HIF\u20101<jats:italic>\u03b1<\/jats:italic>) expression <jats:italic>in vivo<\/jats:italic>. The results suggest that SIRT3 may be an upstream regulator of HIF\u20101<jats:italic>\u03b1<\/jats:italic> expression. Knockdown of SIRT3 resulted in excessive mitochondrial fission and increased oxidative stress <jats:italic>in vitro<\/jats:italic>, and we found that knocking down the expression of HIF\u20101<jats:italic>\u03b1<\/jats:italic> alleviated these changes. This suggests that the SIRT3\u2010HIF\u20101<jats:italic>\u03b1<\/jats:italic> signaling pathway is involved in regulating mitochondrial function and oxidative stress. Furthermore, inhibition of dynamin\u2010related protein 1 (Drp\u20101) by the inhibitor of mitophagy, Mdivi\u20101, blocked mitochondrial fission and alleviated oxidative stress <jats:italic>in vitro<\/jats:italic>. 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.<\/jats:p>","DOI":"10.1155\/2022\/9041914","type":"journal-article","created":{"date-parts":[[2022,9,29]],"date-time":"2022-09-29T23:50:20Z","timestamp":1664495420000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Downregulation of SIRT3 Aggravates Lung Ischemia Reperfusion Injury by Increasing Mitochondrial Fission and Oxidative Stress through HIF\u20101<i>\u03b1<\/i>\u2010Dependent 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