Journal article
Sirt3-Mediated Deacetylation of Evolutionarily Conserved Lysine 122 Regulates MnSOD Activity in Response to Stress
Molecular cell, Vol.40(6), pp.893-904
12/22/2010
DOI: 10.1016/j.molcel.2010.12.013
PMCID: PMC3266626
PMID: 21172655
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. Re-introduction 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 micro-vacuolization in their hepatocytes.
Details
- Title: Subtitle
- Sirt3-Mediated Deacetylation of Evolutionarily Conserved Lysine 122 Regulates MnSOD Activity in Response to Stress
- Creators
- Randa Tao - Molecular Radiation Oncology, Radiation Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USAMitchell C Coleman - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USADaniel Pennington - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USAOzkan Ozden - Departments of Radiation Oncology and Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USASeong-Hoon Park - Departments of Radiation Oncology and Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USAHaiyan Jiang - Departments of Radiation Oncology and Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USAHyun-Seok Kim - Molecular Radiation Oncology, Radiation Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USACharles Robb Flynn - Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USASalisha Hill - Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USAW. Hayes McDonald - Mass Spectrometry Research Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USAAlicia K Olivier - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USADouglas R Spitz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USADavid Gius - Departments of Radiation Oncology and Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Resource Type
- Journal article
- Publication Details
- Molecular cell, Vol.40(6), pp.893-904
- DOI
- 10.1016/j.molcel.2010.12.013
- PMID
- 21172655
- PMCID
- PMC3266626
- ISSN
- 1097-2765
- eISSN
- 1097-4164
- Language
- English
- Date published
- 12/22/2010
- Academic Unit
- Pathology; Orthopedics and Rehabilitation; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984040237502771
Metrics
25 Record Views