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Molecular and Cellular Biology, December 2007, p. 8807-8814, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.01636-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mammalian Sir2 Homolog SIRT3 Regulates Global Mitochondrial Lysine Acetylation{triangledown} ,{dagger}

David B. Lombard,1,2,{ddagger} Frederick W. Alt,1* Hwei-Ling Cheng,1 Jakob Bunkenborg,3 Ryan S. Streeper,4,§ Raul Mostoslavsky,1 Jennifer Kim,1 George Yancopoulos,5 David Valenzuela,5 Andrew Murphy,5 Yinhua Yang,6,¶ Yaohui Chen,6,|| Matthew D. Hirschey,10 Roderick T. Bronson,7 Marcia Haigis,8,# Leonard P. Guarente,8 Robert V. Farese Jr.,4,9 Sherman Weissman,6 Eric Verdin,10* and Bjoern Schwer1,10,{ddagger}

Howard Hughes Medical Institute, The Children's Hospital, Immune Disease Institute, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115,1 Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115,2 Center for Experimental Bioinformatics, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense University, DK-5230 Odense M, Denmark,3 Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94158,4 Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591,5 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06519,6 Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115,7 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139,8 Cardiovascular Research Institute, Departments of Medicine and Biochemistry & Biophysics, and Diabetes Center, University of California, San Francisco, California 94143,9 Gladstone Institute of Virology and Immunology, University of California, San Francisco, California 94158,10

Received 4 September 2007/ Accepted 30 September 2007

Homologs of the Saccharomyces cerevisiae Sir2 protein, sirtuins, promote longevity in many organisms. Studies of the sirtuin SIRT3 have so far been limited to cell culture systems. Here, we investigate the localization and function of SIRT3 in vivo. We show that endogenous mouse SIRT3 is a soluble mitochondrial protein. To address the function and relevance of SIRT3 in the regulation of energy metabolism, we generated and phenotypically characterized SIRT3 knockout mice. SIRT3-deficient animals exhibit striking mitochondrial protein hyperacetylation, suggesting that SIRT3 is a major mitochondrial deacetylase. In contrast, no mitochondrial hyperacetylation was detectable in mice lacking the two other mitochondrial sirtuins, SIRT4 and SIRT5. Surprisingly, despite this biochemical phenotype, SIRT3-deficient mice are metabolically unremarkable under basal conditions and show normal adaptive thermogenesis, a process previously suggested to involve SIRT3. Overall, our results extend the recent finding of lysine acetylation of mitochondrial proteins and demonstrate that SIRT3 has evolved to control reversible lysine acetylation in this organelle.

* Corresponding author. Mailing address for Frederick W. Alt: Howard Hughes Medical Institute, The Children's Hospital, Immune Disease Institute, Harvard Medical School, Boston, MA 02115. Phone: (617) 919-2539. Fax: (617) 730-0948. E-mail: alt{at}enders.tch.harvard.edu. Mailing address for Eric Verdin: Gladstone Institute of Virology and Immunology, University of California, P.O. Box 419100, San Francisco, CA 94158. Phone: (415) 695-3815. Fax: (415) 355-0855. E-mail: everdin{at}gladstone.ucsf.edu

{triangledown} Published ahead of print on 8 October 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally to this work.

§ Present address: Diabetes and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Cambridge, MA 02139.

Present address: Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.

|| Present address: Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.

# Present address: Department of Pathology, Harvard Medical School, Boston, MA 02115.

Molecular and Cellular Biology, December 2007, p. 8807-8814, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.01636-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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