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EMBO Rep. 2011 Jul 1;12(8):840-6. doi: 10.1038/embor.2011.121.

SIRT3-dependent deacetylation exacerbates acetaminophen hepatotoxicity.

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1
Center for Molecular Medicine, NHLBI, National Institutes of Health, Building 10-CRC, Room 5-3150, 10 Center Drive, Bethesda, Maryland 20892, USA.

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.

PMID:
21720390
PMCID:
PMC3147261
DOI:
10.1038/embor.2011.121
[Indexed for MEDLINE]
Free PMC Article
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