Sirt3-Mediated Deacetylation of Evolutionarily Conserved Lysine 122 Regulates MnSOD Activity in Response to Stress

Randa Tao, Mitchell C. Coleman, J. Daniel Pennington, Ozkan Ozden, Seong Hoon Park, Haiyan Jiang, Hyun Seok Kim, Charles Robb Flynn, Salisha Hill, W. Hayes McDonald, Alicia K. Olivier, Douglas R. Spitz, David Gius*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

587 Scopus citations

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-MnSODK122-R), increased MnSOD activity when expressed in MnSOD-/- MEFs, suggesting acetylation directly regulates function. Furthermore, infection of Sirt3-/- MEFs with lenti-MnSODK122-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.

Original languageEnglish (US)
Pages (from-to)893-904
Number of pages12
JournalMolecular cell
Volume40
Issue number6
DOIs
StatePublished - Dec 22 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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