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

815 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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10.1016/j.molcel.2010.12.013

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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. ",

year = "2010",

month = dec,

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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.

UR - https://www.scopus.com/pages/publications/78650248160

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 -

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

Abstract

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