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.
Lombard
David B
DB
Howard Hughes Medical Institute, The Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Alt
Frederick W
FW
Cheng
Hwei-Ling
HL
Bunkenborg
Jakob
J
Streeper
Ryan S
RS
Mostoslavsky
Raul
R
Kim
Jennifer
J
Yancopoulos
George
G
Valenzuela
David
D
Murphy
Andrew
A
Yang
Yinhua
Y
Chen
Yaohui
Y
Hirschey
Matthew D
MD
Bronson
Roderick T
RT
Haigis
Marcia
M
Guarente
Leonard P
LP
Farese
Robert V
RV
Weissman
Sherman
S
Verdin
Eric
E
Schwer
Bjoern
B
D000107:Acetylation; D002001:Adipose Tissue, Brown / Q000166:cytology; D000818:Animals; D005247:Feeding Behavior; D005508:Food Deprivation; D018390:Gene Targeting; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008322:Mammals / Q000378:metabolism*; D051379:Mice; D008930:Mitochondria, Liver / Q000201:enzymology / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000378:metabolism*; D056565:Sirtuin 2; D056566:Sirtuin 3; D037761:Sirtuins / Q000172:deficiency / Q000378:metabolism*; D012995:Solubility; D022722:Thermogenesis
D024101:Mitochondrial Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C525046:Sirt3 protein, mouse; D005969:Glutamate Dehydrogenase; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2; D056566:Sirtuin 3; D037761:Sirtuins; D006655:Histone Deacetylases; D008239:Lysine