title: A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis.
abstract: Here, we demonstrate a role for the mitochondrial NAD-dependent deacetylase Sirt3 in the maintenance of basal ATP levels and as a regulator of mitochondrial electron transport. We note that Sirt3(-/-) mouse embryonic fibroblasts have a reduction in basal ATP levels. Reconstitution with wild-type but not a deacetylase-deficient form of Sirt3 restored ATP levels in these cells. Furthermore in wild-type mice, the resting level of ATP correlates with organ-specific Sirt3 protein expression. Remarkably, in mice lacking Sirt3, basal levels of ATP in the heart, kidney, and liver were reduced >50%. We further demonstrate that mitochondrial protein acetylation is markedly elevated in Sirt3(-/-) tissues. In addition, in the absence of Sirt3, multiple components of Complex I of the electron transport chain demonstrate increased acetylation. Sirt3 can also physically interact with at least one of the known subunits of Complex I, the 39-kDa protein NDUFA9. Functional studies demonstrate that mitochondria from Sirt3(-/-) animals display a selective inhibition of Complex I activity. Furthermore, incubation of exogenous Sirt3 with mitochondria can augment Complex I activity. These results implicate protein acetylation as an important regulator of Complex I activity and demonstrate that Sirt3 functions in vivo to regulate and maintain basal ATP levels.
authors.affiliation: Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Bong-Hyun
authors.initials: BH
authors.lastname: Ahn
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Kim
authors.forename: Shiwei
authors.initials: S
authors.lastname: Song
authors.forename: In Hye
authors.initials: IH
authors.lastname: Lee
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Athanassios
authors.initials: A
authors.lastname: Vassilopoulos
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
mesh_terms: D000107:Acetylation; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D042967:Electron Transport Complex I / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D056566:Sirtuin 3; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; C525046:Sirt3 protein, mouse; D000255:Adenosine Triphosphate; D056566:Sirtuin 3; D037761:Sirtuins; D042967:Electron Transport Complex I
references.citation: Nat Genet. 1999 May;22(1):37-43
references.pmid: 10319859
references.citation: Circ Res. 2004 Jul 23;95(2):135-45
references.pmid: 15271865
references.citation: Genes Dev. 2007 Apr 15;21(8):920-8
references.pmid: 17437997
references.citation: Cell. 2001 Oct 19;107(2):149-59
references.pmid: 11672523
references.citation: Biochim Biophys Acta. 2004 Dec 6;1659(2-3):206-11
references.pmid: 15576053
references.citation: Genes Dev. 2006 Nov 1;20(21):2913-21
references.pmid: 17079682
references.citation: Genes Dev. 1999 Oct 1;13(19):2570-80
references.pmid: 10521401
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13653-8
references.pmid: 12374852
references.citation: Mol Cell. 2006 Aug;23(4):607-18
references.pmid: 16916647
references.citation: Free Radic Res. 2007 Nov;41(11):1212-23
references.pmid: 17907001
references.citation: Nature. 2001 Mar 8;410(6825):227-30
references.pmid: 11242085
references.citation: J Cell Biol. 2002 Aug 19;158(4):647-57
references.pmid: 12186850
references.citation: J Pediatr Surg. 1999 Jul;34(7):1107-11
references.pmid: 10442601
references.citation: Cell. 2006 Sep 8;126(5):941-54
references.pmid: 16959573
references.citation: Mol Cell Biol. 2007 Dec;27(24):8807-14
references.pmid: 17923681
references.citation: Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5860-5
references.pmid: 8650183
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10230-10235
references.pmid: 16790548
references.citation: Biochim Biophys Acta. 2006 Feb;1762(2):213-22
references.pmid: 16120479
references.citation: Nature. 2002 Jul 18;418(6895):344-8
references.pmid: 12124627
references.citation: Free Radic Biol Med. 1999 Jan;26(1-2):3-13
references.pmid: 9890635
references.citation: Cell. 2001 Oct 19;107(2):137-48
references.pmid: 11672522
references.citation: Cell. 1996 Mar 22;84(6):911-21
references.pmid: 8601314
references.citation: J Biol Chem. 2005 Apr 8;280(14):13560-7
references.pmid: 15653680
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3667-72
references.pmid: 9520423
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10224-10229
references.pmid: 16788062
references.citation: Genetics. 1987 May;116(1):9-22
references.pmid: 3297920