Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Mol Cell 2011 Jan 21;41(2):139-49
Date
01/25/2011Pubmed ID
21255725Pubmed Central ID
PMC3101115DOI
10.1016/j.molcel.2011.01.002Scopus ID
2-s2.0-78651468707 (requires institutional sign-in at Scopus site) 317 CitationsAbstract
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 JMAuthor
Brian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AcetylationAnimals
Caloric Restriction
Energy Metabolism
Fatty Acids
HEK293 Cells
Humans
Liver
Mice
Mice, Inbred Strains
Mitochondria
Ornithine Carbamoyltransferase
Oxidation-Reduction
Sirtuin 3
Urea
