TY - JOUR
T1 - Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation
AU - Lombard, David B.
AU - Alt, Frederick W.
AU - Cheng, Hwei Ling
AU - Bunkenborg, Jakob
AU - Streeper, Ryan S.
AU - Mostoslavsky, Raul
AU - Kim, Jennifer
AU - Yancopoulos, George
AU - Valenzuela, David
AU - Murphy, Andrew
AU - Yang, Yinhua
AU - Chen, Yaohui
AU - Hirschey, Matthew D.
AU - Bronson, Roderick T.
AU - Haigis, Marcia
AU - Guarente, Leonard P.
AU - Farese, Robert V.
AU - Weissman, Sherman
AU - Verdin, Eric
AU - Schwer, Bjoern
PY - 2007/12
Y1 - 2007/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=37549002891&partnerID=8YFLogxK
U2 - 10.1128/MCB.01636-07
DO - 10.1128/MCB.01636-07
M3 - Article
C2 - 17923681
AN - SCOPUS:37549002891
SN - 0270-7306
VL - 27
SP - 8807
EP - 8814
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 24
ER -