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

Research output: Contribution to journalArticlepeer-review

752 Scopus citations


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
Pages (from-to)893-904
Number of pages12
JournalMolecular Cell
Issue number6
StatePublished - 22 Dec 2010

Bibliographical note

Funding Information:
D.G. is supported by 1R01CA152601-01 from the NCI, BC093803 from the DOD, and SPORE P50CA98131. D.R.S., A.K.O., and M.C.C. are supported by grants from the NIH and DOE (R01CA133114, T32CA078586, P30CA086862, and DE-SC0000830). J.D.P. is supported by F30AG030839. We thank Melissa Stauffer of Scientific Editing Solutions for editorial assistance.


Dive into the research topics of 'Sirt3-Mediated Deacetylation of Evolutionarily Conserved Lysine 122 Regulates MnSOD Activity in Response to Stress'. Together they form a unique fingerprint.

Cite this