SIRT3 Is a Mitochondria-Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism during Stress

Hyun Seok Kim; Krish Patel; Kristi Muldoon-Jacobs; Kheem S. Bisht; Nukhet Aykin-Burns; J. Daniel Pennington; Riet van der Meer; Phuongmai Nguyen; Jason Savage; Kjerstin M. Owens; Athanassios Vassilopoulos; Ozkan Ozden; Seong Hoon Park; Keshav K. Singh; Sarki A. Abdulkadir; Douglas R. Spitz; Chu Xia Deng; David Gius

doi:10.1016/j.ccr.2009.11.023

SIRT3 Is a Mitochondria-Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism during Stress

Hyun Seok Kim, Krish Patel, Kristi Muldoon-Jacobs, Kheem S. Bisht, Nukhet Aykin-Burns, J. Daniel Pennington, Riet van der Meer, Phuongmai Nguyen, Jason Savage, Kjerstin M. Owens, Athanassios Vassilopoulos, Ozkan Ozden, Seong Hoon Park, Keshav K. Singh, Sarki A. Abdulkadir, Douglas R. Spitz, Chu Xia Deng, David Gius

Department of Life Science

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

686 Scopus citations

Abstract

The sirtuin gene family (SIRT) is hypothesized to regulate the aging process and play a role in cellular repair. This work demonstrates that SIRT3^-/- mouse embryonic fibroblasts (MEFs) exhibit abnormal mitochondrial physiology as well as increases in stress-induced superoxide levels and genomic instability. Expression of a single oncogene (Myc or Ras) in SIRT3^-/- MEFs results in in vitro transformation and altered intracellular metabolism. Superoxide dismutase prevents transformation by a single oncogene in SIRT3^-/- MEFs and reverses the tumor-permissive phenotype as well as stress-induced genomic instability. In addition, SIRT3^-/- mice develop ER/PR-positive mammary tumors. Finally, human breast and other human cancer specimens exhibit reduced SIRT3 levels. These results identify SIRT3 as a genomically expressed, mitochondria-localized tumor suppressor.

Original language	English
Pages (from-to)	41-52
Number of pages	12
Journal	Cancer Cell
Volume	17
Issue number	1
DOIs	https://doi.org/10.1016/j.ccr.2009.11.023
State	Published - 19 Jan 2010

Bibliographical note

Funding Information:
This research was supported (in part) by the Intramural Research Program of the National Institute Diabetes and Digestive and Kidney Diseases, National Cancer Institute, and CCR, National Institutes of Health. D.R.S. and N.A.B. are supported by grants from the National Institutes of Health (R01CA100045, R01CA133114, and P30 CA086862). K.K.S. was supported by R01 121904 and 116430. J.D.S. was supported by F30AG030839. S.A.A. was supported by CA094858 and CA123484. We thank Melissa Stauffer, PhD, of Scientific Editing Solutions, for editorial assistance.

Keywords

CELLCYCLE
PROTEINS

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10.1016/j.ccr.2009.11.023

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Kim, H. S., Patel, K., Muldoon-Jacobs, K., Bisht, K. S., Aykin-Burns, N., Pennington, J. D., van der Meer, R., Nguyen, P., Savage, J., Owens, K. M., Vassilopoulos, A., Ozden, O., Park, S. H., Singh, K. K., Abdulkadir, S. A., Spitz, D. R., Deng, C. X., & Gius, D. (2010). SIRT3 Is a Mitochondria-Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism during Stress. Cancer Cell, 17(1), 41-52. https://doi.org/10.1016/j.ccr.2009.11.023

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title = "SIRT3 Is a Mitochondria-Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism during Stress",

abstract = "The sirtuin gene family (SIRT) is hypothesized to regulate the aging process and play a role in cellular repair. This work demonstrates that SIRT3-/- mouse embryonic fibroblasts (MEFs) exhibit abnormal mitochondrial physiology as well as increases in stress-induced superoxide levels and genomic instability. Expression of a single oncogene (Myc or Ras) in SIRT3-/- MEFs results in in vitro transformation and altered intracellular metabolism. Superoxide dismutase prevents transformation by a single oncogene in SIRT3-/- MEFs and reverses the tumor-permissive phenotype as well as stress-induced genomic instability. In addition, SIRT3-/- mice develop ER/PR-positive mammary tumors. Finally, human breast and other human cancer specimens exhibit reduced SIRT3 levels. These results identify SIRT3 as a genomically expressed, mitochondria-localized tumor suppressor.",

keywords = "CELLCYCLE, PROTEINS",

author = "Kim, {Hyun Seok} and Krish Patel and Kristi Muldoon-Jacobs and Bisht, {Kheem S.} and Nukhet Aykin-Burns and Pennington, {J. Daniel} and {van der Meer}, Riet and Phuongmai Nguyen and Jason Savage and Owens, {Kjerstin M.} and Athanassios Vassilopoulos and Ozkan Ozden and Park, {Seong Hoon} and Singh, {Keshav K.} and Abdulkadir, {Sarki A.} and Spitz, {Douglas R.} and Deng, {Chu Xia} and David Gius",

note = "Funding Information: This research was supported (in part) by the Intramural Research Program of the National Institute Diabetes and Digestive and Kidney Diseases, National Cancer Institute, and CCR, National Institutes of Health. D.R.S. and N.A.B. are supported by grants from the National Institutes of Health (R01CA100045, R01CA133114, and P30 CA086862). K.K.S. was supported by R01 121904 and 116430. J.D.S. was supported by F30AG030839. S.A.A. was supported by CA094858 and CA123484. We thank Melissa Stauffer, PhD, of Scientific Editing Solutions, for editorial assistance. ",

year = "2010",

month = jan,

day = "19",

doi = "10.1016/j.ccr.2009.11.023",

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Kim, HS, Patel, K, Muldoon-Jacobs, K, Bisht, KS, Aykin-Burns, N, Pennington, JD, van der Meer, R, Nguyen, P, Savage, J, Owens, KM, Vassilopoulos, A, Ozden, O, Park, SH, Singh, KK, Abdulkadir, SA, Spitz, DR, Deng, CX & Gius, D 2010, 'SIRT3 Is a Mitochondria-Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism during Stress', Cancer Cell, vol. 17, no. 1, pp. 41-52. https://doi.org/10.1016/j.ccr.2009.11.023

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AU - Kim, Hyun Seok

AU - Patel, Krish

AU - Muldoon-Jacobs, Kristi

AU - Bisht, Kheem S.

AU - Aykin-Burns, Nukhet

AU - Pennington, J. Daniel

AU - van der Meer, Riet

AU - Nguyen, Phuongmai

AU - Savage, Jason

AU - Owens, Kjerstin M.

AU - Vassilopoulos, Athanassios

AU - Ozden, Ozkan

AU - Park, Seong Hoon

AU - Singh, Keshav K.

AU - Abdulkadir, Sarki A.

AU - Spitz, Douglas R.

AU - Deng, Chu Xia

AU - Gius, David

N1 - Funding Information: This research was supported (in part) by the Intramural Research Program of the National Institute Diabetes and Digestive and Kidney Diseases, National Cancer Institute, and CCR, National Institutes of Health. D.R.S. and N.A.B. are supported by grants from the National Institutes of Health (R01CA100045, R01CA133114, and P30 CA086862). K.K.S. was supported by R01 121904 and 116430. J.D.S. was supported by F30AG030839. S.A.A. was supported by CA094858 and CA123484. We thank Melissa Stauffer, PhD, of Scientific Editing Solutions, for editorial assistance.

PY - 2010/1/19

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N2 - The sirtuin gene family (SIRT) is hypothesized to regulate the aging process and play a role in cellular repair. This work demonstrates that SIRT3-/- mouse embryonic fibroblasts (MEFs) exhibit abnormal mitochondrial physiology as well as increases in stress-induced superoxide levels and genomic instability. Expression of a single oncogene (Myc or Ras) in SIRT3-/- MEFs results in in vitro transformation and altered intracellular metabolism. Superoxide dismutase prevents transformation by a single oncogene in SIRT3-/- MEFs and reverses the tumor-permissive phenotype as well as stress-induced genomic instability. In addition, SIRT3-/- mice develop ER/PR-positive mammary tumors. Finally, human breast and other human cancer specimens exhibit reduced SIRT3 levels. These results identify SIRT3 as a genomically expressed, mitochondria-localized tumor suppressor.

AB - The sirtuin gene family (SIRT) is hypothesized to regulate the aging process and play a role in cellular repair. This work demonstrates that SIRT3-/- mouse embryonic fibroblasts (MEFs) exhibit abnormal mitochondrial physiology as well as increases in stress-induced superoxide levels and genomic instability. Expression of a single oncogene (Myc or Ras) in SIRT3-/- MEFs results in in vitro transformation and altered intracellular metabolism. Superoxide dismutase prevents transformation by a single oncogene in SIRT3-/- MEFs and reverses the tumor-permissive phenotype as well as stress-induced genomic instability. In addition, SIRT3-/- mice develop ER/PR-positive mammary tumors. Finally, human breast and other human cancer specimens exhibit reduced SIRT3 levels. These results identify SIRT3 as a genomically expressed, mitochondria-localized tumor suppressor.

KW - CELLCYCLE

KW - PROTEINS

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M3 - Article

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AN - SCOPUS:74049094817

SN - 1535-6108

VL - 17

SP - 41

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JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

SIRT3 Is a Mitochondria-Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism during Stress

Abstract

Bibliographical note

Keywords

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