PMID- 20203611
OWN - NLM
STAT- MEDLINE
DCOM- 20100419
LR  - 20221109
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 464
IP  - 7285
DP  - 2010 Mar 4
TI  - SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme 
      deacetylation.
PG  - 121-5
LID - 10.1038/nature08778 [doi]
AB  - Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive 
      responses to a variety of stresses, including calorie restriction and metabolic 
      stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it 
      regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme 
      A synthetase 2 (refs 1, 2). Mice lacking both Sirt3 alleles appear phenotypically 
      normal under basal conditions, but show marked hyperacetylation of several 
      mitochondrial proteins. Here we report that SIRT3 expression is upregulated 
      during fasting in liver and brown adipose tissues. During fasting, livers from 
      mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate 
      products and triglycerides, associated with decreased levels of fatty-acid 
      oxidation, compared to livers from wild-type mice. Mass spectrometry of 
      mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) 
      is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in 
      wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo; and 
      hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 
      exhibit hallmarks of fatty-acid oxidation disorders during fasting, including 
      reduced ATP levels and intolerance to cold exposure. These findings identify 
      acetylation as a novel regulatory mechanism for mitochondrial fatty-acid 
      oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary 
      metabolism and fatty-acid use during fasting.
FAU - Hirschey, Matthew D
AU  - Hirschey MD
AD  - Gladstone Institute of Virology and Immunology, San Francisco, California 94158, 
      USA.
FAU - Shimazu, Tadahiro
AU  - Shimazu T
FAU - Goetzman, Eric
AU  - Goetzman E
FAU - Jing, Enxuan
AU  - Jing E
FAU - Schwer, Bjoern
AU  - Schwer B
FAU - Lombard, David B
AU  - Lombard DB
FAU - Grueter, Carrie A
AU  - Grueter CA
FAU - Harris, Charles
AU  - Harris C
FAU - Biddinger, Sudha
AU  - Biddinger S
FAU - Ilkayeva, Olga R
AU  - Ilkayeva OR
FAU - Stevens, Robert D
AU  - Stevens RD
FAU - Li, Yu
AU  - Li Y
FAU - Saha, Asish K
AU  - Saha AK
FAU - Ruderman, Neil B
AU  - Ruderman NB
FAU - Bain, James R
AU  - Bain JR
FAU - Newgard, Christopher B
AU  - Newgard CB
FAU - Farese, Robert V Jr
AU  - Farese RV Jr
FAU - Alt, Frederick W
AU  - Alt FW
FAU - Kahn, C Ronald
AU  - Kahn CR
FAU - Verdin, Eric
AU  - Verdin E
LA  - eng
GR  - R01 DK019514-29/DK/NIDDK NIH HHS/United States
GR  - P30 DK026743/DK/NIDDK NIH HHS/United States
GR  - K08 AG022325/AG/NIA NIH HHS/United States
GR  - P30 DK026743-26A1/DK/NIDDK NIH HHS/United States
GR  - K01 DK076573/DK/NIDDK NIH HHS/United States
GR  - P01 HL068758-06A1/HL/NHLBI NIH HHS/United States
GR  - DK59637/DK/NIDDK NIH HHS/United States
GR  - U24 DK059637-01/DK/NIDDK NIH HHS/United States
GR  - P01 HL068758/HL/NHLBI NIH HHS/United States
GR  - R01 DK067509-04/DK/NIDDK NIH HHS/United States
GR  - U24 DK059637/DK/NIDDK NIH HHS/United States
GR  - R01 DK067509/DK/NIDDK NIH HHS/United States
GR  - K08 AG022325-01A1/AG/NIA NIH HHS/United States
GR  - R01 DK019514/DK/NIDDK NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Fatty Acids)
RN  - 0 (Sirt3 protein, mouse)
RN  - 0 (Triglycerides)
RN  - 0 (acylcarnitine)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 1.3.8.8 (Acyl-CoA Dehydrogenase, Long-Chain)
RN  - EC 3.5.1.- (Sirtuin 3)
RN  - S7UI8SM58A (Carnitine)
SB  - IM
MH  - Acetylation
MH  - Acyl-CoA Dehydrogenase, Long-Chain/chemistry/*metabolism
MH  - Adenosine Triphosphate/biosynthesis/metabolism
MH  - Adipose Tissue, Brown/enzymology/metabolism
MH  - Animals
MH  - Body Temperature Regulation
MH  - Caloric Restriction
MH  - Carnitine/analogs & derivatives/metabolism
MH  - Cell Line
MH  - Cold Temperature
MH  - Fasting/metabolism
MH  - Fatty Acids/*metabolism
MH  - Humans
MH  - Hypoglycemia/metabolism
MH  - Liver/enzymology/metabolism
MH  - Male
MH  - Mass Spectrometry
MH  - Mice
MH  - Mitochondria/*enzymology/*metabolism
MH  - Oxidation-Reduction
MH  - Sirtuin 3/deficiency/genetics/*metabolism
MH  - Triglycerides/metabolism
MH  - Up-Regulation
PMC - PMC2841477
MID - NIHMS166711
EDAT- 2010/03/06 06:00
MHDA- 2010/04/20 06:00
PMCR- 2010/09/04
CRDT- 2010/03/06 06:00
PHST- 2008/12/17 00:00 [received]
PHST- 2009/12/21 00:00 [accepted]
PHST- 2010/03/06 06:00 [entrez]
PHST- 2010/03/06 06:00 [pubmed]
PHST- 2010/04/20 06:00 [medline]
PHST- 2010/09/04 00:00 [pmc-release]
AID - nature08778 [pii]
AID - 10.1038/nature08778 [doi]
PST - ppublish
SO  - Nature. 2010 Mar 4;464(7285):121-5. doi: 10.1038/nature08778.