title: Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress.
abstract: Genetic deletion of the mitochondrial deacetylase sirtuin-3 (Sirt3) results in increased mitochondrial superoxide, a tumor-permissive environment, and mammary tumor development. MnSOD contains a nutrient- and ionizing radiation (IR)-dependent reversible acetyl-lysine that is hyperacetylated in Sirt3⁻/⁻ livers at 3 months of age. Livers of Sirt3⁻/⁻ mice exhibit decreased MnSOD activity, but not immunoreactive protein, relative to wild-type livers. Reintroduction of wild-type but not deacetylation null Sirt3 into Sirt3⁻/⁻ MEFs deacetylated lysine and restored MnSOD activity. Site-directed mutagenesis of MnSOD lysine 122 to an arginine, mimicking deacetylation (lenti-MnSOD(K122-R)), increased MnSOD activity when expressed in MnSOD⁻/⁻ MEFs, suggesting acetylation directly regulates function. Furthermore, infection of Sirt3⁻/⁻ MEFs with lenti-MnSOD(K122-R) inhibited in vitro immortalization by an oncogene (Ras), inhibited IR-induced genomic instability, and decreased mitochondrial superoxide. Finally, IR was unable to induce MnSOD deacetylation or activity in Sirt3⁻/⁻ livers, and these irradiated livers displayed significant IR-induced cell damage and microvacuolization in their hepatocytes.
authors.affiliation: Howard Hughes Medical Institute and Molecular Radiation Oncology, Radiation Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
authors.forename: Randa
authors.initials: R
authors.lastname: Tao
authors.forename: Mitchell C
authors.initials: MC
authors.lastname: Coleman
authors.forename: J Daniel
authors.initials: JD
authors.lastname: Pennington
authors.forename: Ozkan
authors.initials: O
authors.lastname: Ozden
authors.forename: Seong-Hoon
authors.initials: SH
authors.lastname: Park
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Kim
authors.forename: Charles Robb
authors.initials: CR
authors.lastname: Flynn
authors.forename: Salisha
authors.initials: S
authors.lastname: Hill
authors.forename: W
authors.initials: W
authors.lastname: Hayes McDonald
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Olivier
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Spitz
authors.forename: David
authors.initials: D
authors.lastname: Gius
mesh_terms: D000107:Acetylation; D000818:Animals; D001120:Arginine / Q000378:metabolism; D002460:Cell Line; D017124:Conserved Sequence; D019143:Evolution, Molecular; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D018384:Oxidative Stress; D056566:Sirtuin 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: C525046:Sirt3 protein, mouse; D001120:Arginine; D013482:Superoxide Dismutase; D056566:Sirtuin 3; D008239:Lysine