Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction.
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.
Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI 53706, USA.
William C
WC
Hallows
Wei
W
Yu
Brian C
BC
Smith
Mark K
MK
Devries
Mark K
MK
Devires
James J
JJ
Ellinger
Shinichi
S
Someya
Michael R
MR
Shortreed
Tomas
T
Prolla
John L
JL
Markley
Lloyd M
LM
Smith
Shimin
S
Zhao
Kun-Liang
KL
Guan
John M
JM
Denu
D000107:Acetylation; D000818:Animals; D031204:Caloric Restriction; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000378:metabolism; D009954:Ornithine Carbamoyltransferase / Q000378:metabolism*; D010084:Oxidation-Reduction; D056566:Sirtuin 3 / Q000378:metabolism / Q000502:physiology*; D014508:Urea / Q000378:metabolism*
D005227:Fatty Acids; C525046:Sirt3 protein, mouse; D014508:Urea; D009954:Ornithine Carbamoyltransferase; D056566:Sirtuin 3
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