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

被引：776

作者：

Tao, Randa ^{[3
,4
]}

Coleman, Mitchell C. ^{[5
]}

Pennington, J. Daniel ^{[3
,4
]}

Ozden, Ozkan ^{[1
,2
]}

Park, Seong-Hoon ^{[1
,2
]}

Jiang, Haiyan ^{[1
,2
]}

Kim, Hyun-Seok ^{[1
,2
]}

Flynn, Charles Robb ^{[7
]}

Hill, Salisha ^{[8
]}

McDonald, W. Hayes ^{[8
]}

Olivier, Alicia K. ^{[6
]}

Spitz, Douglas R. ^{[5
]}

Gius, David ^{[1
,2
]}

机构：

[1] Vanderbilt Univ, Med Ctr, Dept Radiat Oncol, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA

[3] Howard Hughes Med Inst, Bethesda, MD 20892 USA

[4] NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[5] Univ Iowa, Holden Comprehens Canc Ctr, Dept Radiat Oncol, Free Rad & Radiat Biol Program, Iowa City, IA 52242 USA

[6] Univ Iowa, Carver Coll Med, Dept Pathol, Iowa City, IA 52242 USA

[7] Vanderbilt Univ, Dept Surg, Sch Med, Nashville, TN 37232 USA

[8] Vanderbilt Univ, Mass Spectrometry Res Ctr, Sch Med, Nashville, TN 37232 USA

来源：

MOLECULAR CELL | 2010年 / 40卷 / 06期

关键词：

SIR2; HOMOLOG; MITOCHONDRIA; SUPEROXIDE; CANCER;

D O I：

10.1016/j.molcel.2010.12.013

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 (lR)-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.

引用

页码：893 / 904

页数：12

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