SIRT3‐dependent deacetylation exacerbates acetaminophen hepatotoxicity

Z Lu, M Bourdi, JH Li, AM Aponte, Y Chen… - EMBO …, 2011 - embopress.org
Z Lu, M Bourdi, JH Li, AM Aponte, Y Chen, DB Lombard, M Gucek, LR Pohl, MN Sack
EMBO reports, 2011embopress.org
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 …
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.
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