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SIRT3‐dependent deacetylation exacerbates acetaminophen hepatotoxicity
Author(s) -
Lu Zhongping,
Bourdi Mohammed,
Li Jian H,
Aponte Angel M,
Chen Yong,
Lombard David B,
Gucek Marjan,
Pohl Lance R,
Sack Michael N
Publication year - 2011
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/embor.2011.121
Subject(s) - acetylation , sirt3 , acetaminophen , chemistry , sirtuin , biochemistry , gene
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.