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SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation.

Nature | Mar 4, 2010

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.

Pubmed ID: 20203611 RIS Download

Mesh terms: Acetylation | Acyl-CoA Dehydrogenase, Long-Chain | Adenosine Triphosphate | Adipose Tissue, Brown | Animals | Body Temperature Regulation | Caloric Restriction | Carnitine | Cell Line | Cold Temperature | Fasting | Fatty Acids | Humans | Hypoglycemia | Liver | Male | Mass Spectrometry | Mice | Mitochondria | Oxidation-Reduction | Sirtuin 3 | Triglycerides | Up-Regulation

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Associated grants

  • Agency: NIDDK NIH HHS, Id: R01 DK067509
  • Agency: NIA NIH HHS, Id: K08 AG022325-01A1
  • Agency: NIDDK NIH HHS, Id: R01 DK019514-29
  • Agency: NIDDK NIH HHS, Id: P30 DK026743
  • Agency: NIA NIH HHS, Id: K08 AG022325
  • Agency: NIDDK NIH HHS, Id: P30 DK026743-26A1
  • Agency: NIDDK NIH HHS, Id: K01 DK076573
  • Agency: NHLBI NIH HHS, Id: P01 HL068758-06A1
  • Agency: Howard Hughes Medical Institute, Id: DK59637
  • Agency: NIDDK NIH HHS, Id: U24 DK059637-01
  • Agency: NIDDK NIH HHS, Id: P01 HL068758
  • Agency: NHLBI NIH HHS, Id: R01 DK067509-04
  • Agency: NIDDK NIH HHS, Id: R01 DK019514
  • Agency: NIDDK NIH HHS, Id: U24 DK059637
  • Agency: NIDDK NIH HHS, Id:

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