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.

journal_name

EMBO Rep

journal_title

EMBO reports

authors

Lu Z,Bourdi M,Li JH,Aponte AM,Chen Y,Lombard DB,Gucek M,Pohl LR,Sack MN

doi

10.1038/embor.2011.121

subject

Has Abstract

pub_date

2011-07-01 00:00:00

pages

840-6

issue

8

eissn

1469-221X

issn

1469-3178

pii

embor2011121

journal_volume

12

pub_type

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