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

doi:10.1016/j.molcel.2010.12.013

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

Department of Life Science

Research output: Contribution to journal › Article › peer-review

768 Scopus citations

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. 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-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 microvacuolization in their hepatocytes.

Original language	English
Pages (from-to)	893-904
Number of pages	12
Journal	Molecular Cell
Volume	40
Issue number	6
DOIs	https://doi.org/10.1016/j.molcel.2010.12.013
State	Published - 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.

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Tao, R., Coleman, M. C., Pennington, J. D., Ozden, O., Park, S. H., Jiang, H., Kim, H. S., Flynn, C. R., Hill, S., McDonald, W. H., Olivier, A. K., Spitz, D. R., & Gius, D. (2010). Sirt3-Mediated Deacetylation of Evolutionarily Conserved Lysine 122 Regulates MnSOD Activity in Response to Stress. Molecular Cell, 40(6), 893-904. https://doi.org/10.1016/j.molcel.2010.12.013

@article{ee0a9533aded41d5b87495f54674f28d,

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

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. 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.",

author = "Randa Tao and Coleman, {Mitchell C.} and Pennington, {J. Daniel} and Ozkan Ozden and Park, {Seong Hoon} and Haiyan Jiang and Kim, {Hyun Seok} and Flynn, {Charles Robb} and Salisha Hill and McDonald, {W. Hayes} and Olivier, {Alicia K.} and Spitz, {Douglas R.} and David Gius",

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. ",

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doi = "10.1016/j.molcel.2010.12.013",

language = "English",

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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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DO - 10.1016/j.molcel.2010.12.013

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AN - SCOPUS:78650248160

SN - 1097-2765

VL - 40

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JO - Molecular Cell

JF - Molecular Cell

IS - 6

ER -

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

Abstract

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