TY - JOUR
T1 - Sirt3-Mediated Deacetylation of Evolutionarily Conserved Lysine 122 Regulates MnSOD Activity in Response to Stress
AU - Tao, Randa
AU - Coleman, Mitchell C.
AU - Pennington, J. Daniel
AU - Ozden, Ozkan
AU - Park, Seong Hoon
AU - Jiang, Haiyan
AU - Kim, Hyun Seok
AU - Flynn, Charles Robb
AU - Hill, Salisha
AU - McDonald, W. Hayes
AU - Olivier, Alicia K.
AU - Spitz, Douglas R.
AU - Gius, David
N1 - 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.
PY - 2010/12/22
Y1 - 2010/12/22
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2010.12.013
DO - 10.1016/j.molcel.2010.12.013
M3 - Article
C2 - 21172655
AN - SCOPUS:78650248160
SN - 1097-2765
VL - 40
SP - 893
EP - 904
JO - Molecular Cell
JF - Molecular Cell
IS - 6
ER -