title: SIRT3-dependent deacetylation exacerbates acetaminophen hepatotoxicity.
abstract: Acetaminophen/paracetamol-induced liver failure--which is induced by the binding of reactive metabolites to mitochondrial proteins and their disruption--is exacerbated by fasting. As fasting promotes SIRT3-mediated mitochondrial-protein deacetylation and acetaminophen metabolites bind to lysine residues, we investigated whether deacetylation predisposes mice to toxic metabolite-mediated disruption of mitochondrial proteins. We show that mitochondrial deacetylase SIRT3(-/-) mice are protected from acetaminophen hepatotoxicity, that mitochondrial aldehyde dehydrogenase 2 is a direct SIRT3 substrate, and that its deacetylation increases acetaminophen toxic-metabolite binding and enzyme inactivation. Thus, protein deacetylation enhances xenobiotic liver injury by modulating the binding of a toxic metabolite to mitochondrial proteins.
authors: Center for Molecular Medicine, NHLBI, National Institutes of Health, Building 10-CRC, Room 5-3150, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors: Zhongping
authors: Z
authors: Lu
authors: Mohammed
authors: M
authors: Bourdi
authors: Jian H
authors: JH
authors: Li
authors: Angel M
authors: AM
authors: Aponte
authors: Yong
authors: Y
authors: Chen
authors: David B
authors: DB
authors: Lombard
authors: Marjan
authors: M
authors: Gucek
authors: Lance R
authors: LR
authors: Pohl
authors: Michael N
authors: MN
authors: Sack
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000107:Acetylation; D000410:Alanine Transaminase / Q000097:blood; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D016227:Benzoquinones / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D007097:Imines / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D011485:Protein Binding; D056566:Sirtuin 3 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016227:Benzoquinones; D007097:Imines; D024101:Mitochondrial Proteins; C525046:Sirt3 protein, mouse; D000082:Acetaminophen; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000410:Alanine Transaminase; D056566:Sirtuin 3; C028473:N-acetyl-4-benzoquinoneimine