Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress.
Mol Cell
; 40(6): 893-904, 2010 Dec 22.
Article
em En
| MEDLINE
| ID: mdl-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 Sirt3â»/â» livers at 3 months of age. Livers of Sirt3â»/â» mice exhibit decreased MnSOD activity, but not immunoreactive protein, relative to wild-type livers. Reintroduction of wild-type but not deacetylation null Sirt3 into Sirt3â»/â» 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 MnSODâ»/â» MEFs, suggesting acetylation directly regulates function. Furthermore, infection of Sirt3â»/â» 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 Sirt3â»/â» livers, and these irradiated livers displayed significant IR-induced cell damage and microvacuolization in their hepatocytes.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Superóxido Dismutase
/
Sequência Conservada
/
Estresse Oxidativo
/
Evolução Molecular
/
Sirtuína 3
/
Lisina
Limite:
Animals
Idioma:
En
Revista:
Mol Cell
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Estados Unidos