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Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Mol Cell 2011 Jan 21;41(2):139-49

Date

01/25/2011

Pubmed ID

21255725

Pubmed Central ID

PMC3101115

DOI

10.1016/j.molcel.2011.01.002

Scopus ID

2-s2.0-78651468707 (requires institutional sign-in at Scopus site)   316 Citations

Abstract

Emerging evidence suggests that protein acetylation is a broad-ranging regulatory mechanism. Here we utilize acetyl-peptide arrays and metabolomic analyses to identify substrates of mitochondrial deacetylase Sirt3. We identified ornithine transcarbamoylase (OTC) from the urea cycle, and enzymes involved in β-oxidation. Metabolomic analyses of fasted mice lacking Sirt3 (sirt3(-/-)) revealed alterations in β-oxidation and the urea cycle. Biochemical analysis demonstrated that Sirt3 directly deacetylates OTC and stimulates its activity. Mice under caloric restriction (CR) increased Sirt3 protein levels, leading to deacetylation and stimulation of OTC activity. In contrast, sirt3(-/-) mice failed to deacetylate OTC in response to CR. Inability to stimulate OTC under CR led to a failure to reduce orotic acid levels, a known outcome of OTC deficiency. Thus, Sirt3 directly regulates OTC activity and promotes the urea cycle during CR, and the results suggest that under low energy input, Sirt3 modulates mitochondria by promoting amino acid catabolism and β-oxidation.

Author List

Hallows WC, Yu W, Smith BC, Devries MK, Ellinger JJ, Someya S, Shortreed MR, Prolla T, Markley JL, Smith LM, Zhao S, Guan KL, Denu JM

Author

Brian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Acetylation
Animals
Caloric Restriction
Energy Metabolism
Fatty Acids
HEK293 Cells
Humans
Liver
Mice
Mice, Inbred Strains
Mitochondria
Ornithine Carbamoyltransferase
Oxidation-Reduction
Sirtuin 3
Urea