title: Sirtuin 1 suppresses mitochondrial dysfunction of ischemic mouse livers in a mitofusin 2-dependent manner.
abstract: Ischemia/reperfusion (I/R) injury is a major cause of morbidity and mortality after liver surgery. The role of Sirtuin 1 (SIRT1) in hepatic I/R injury remains elusive. Using human and mouse livers, we investigated the effects of I/R on hepatocellular SIRT1. SIRT1 expression was significantly decreased after I/R. Genetic overexpression or pharmacological activation of SIRT1 markedly suppressed defective autophagy, onset of the mitochondrial permeability transition, and hepatocyte death after I/R, whereas SIRT1-null hepatocytes exhibited increased sensitivity to I/R injury. Biochemical approaches revealed that SIRT1 interacts with mitofusin-2 (MFN2). Furthermore, MFN2, but not MFN1, was deacetylated by SIRT1. Moreover, SIRT1 overexpression substantially increased autophagy in wild-type cells, but not in MFN2-deficient cells. Thus, our results demonstrate that the loss of SIRT1 causes a sequential chain of defective autophagy, mitochondrial dysfunction, and hepatocyte death after I/R.
authors.affiliation: Department of Surgery, University of Florida, Gainesville, FL, USA.
authors.forename: T G
authors.initials: TG
authors.lastname: Biel
authors.affiliation: Department of Surgery, University of Florida, Gainesville, FL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Surgery, University of Florida, Gainesville, FL, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Flores-Toro
authors.affiliation: Department of Surgery, University of Florida, Gainesville, FL, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Dean
authors.affiliation: Department of Surgery, University of Florida, Gainesville, FL, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Go
authors.affiliation: Department of Surgery, University of Florida, Gainesville, FL, USA.
authors.forename: M-H
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.
authors.forename: B K
authors.initials: BK
authors.lastname: Law
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Law
authors.affiliation: Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Dunn
authors.affiliation: Department of Surgery, University of Florida, Gainesville, FL, USA.
authors.forename: I
authors.initials: I
authors.lastname: Zendejas
authors.affiliation: Department of Surgery, University of Florida, Gainesville, FL, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Behrns
authors.affiliation: Department of Surgery, University of Florida, Gainesville, FL, USA.|Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.|Department of Anatomy and Cell Biology, University of Florida, Gainesville, FL, USA.
authors.forename: J-S
authors.initials: JS
authors.lastname: Kim
mesh_terms: D000818:Animals; D001343:Autophagy; D002154:Calpain / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007511:Ischemia / Q000201:enzymology; D008099:Liver / Q000098:blood supply* / Q000201:enzymology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000201:enzymology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D054730:Protein Interaction Domains and Motifs; D015427:Reperfusion Injury / Q000201:enzymology; D056564:Sirtuin 1 / Q000502:physiology*
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D002154:Calpain; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse