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.
journal_name
EMBO Repjournal_title
EMBO reportsauthors
Lu Z,Bourdi M,Li JH,Aponte AM,Chen Y,Lombard DB,Gucek M,Pohl LR,Sack MNdoi
10.1038/embor.2011.121subject
Has Abstractpub_date
2011-07-01 00:00:00pages
840-6issue
8eissn
1469-221Xissn
1469-3178pii
embor2011121journal_volume
12pub_type
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