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Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation.

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.

Pubmed ID: 17923681


  • Lombard DB
  • Alt FW
  • Cheng HL
  • Bunkenborg J
  • Streeper RS
  • Mostoslavsky R
  • Kim J
  • Yancopoulos G
  • Valenzuela D
  • Murphy A
  • Yang Y
  • Chen Y
  • Hirschey MD
  • Bronson RT
  • Haigis M
  • Guarente LP
  • Farese RV
  • Weissman S
  • Verdin E
  • Schwer B


Molecular and cellular biology

Publication Data

December 27, 2007

Associated Grants

  • Agency: NCRR NIH HHS, Id: 1C06RR18928

Mesh Terms

  • Acetylation
  • Adipose Tissue, Brown
  • Animals
  • Feeding Behavior
  • Food Deprivation
  • Gene Targeting
  • Glutamate Dehydrogenase
  • Histone Deacetylases
  • Lysine
  • Mammals
  • Mice
  • Mitochondria, Liver
  • Mitochondrial Proteins
  • Sequence Homology, Amino Acid
  • Silent Information Regulator Proteins, Saccharomyces cerevisiae
  • Sirtuin 2
  • Sirtuin 3
  • Sirtuins
  • Solubility
  • Thermogenesis