SIRT3-dependent deacetylation exacerbates acetaminophen hepatotoxicity.

Published

Journal Article

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.

Full Text

Cited Authors

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

Published Date

  • July 2011

Published In

Volume / Issue

  • 12 / 8

Start / End Page

  • 840 - 846

PubMed ID

  • 21720390

Pubmed Central ID

  • 21720390

Electronic International Standard Serial Number (EISSN)

  • 1469-3178

International Standard Serial Number (ISSN)

  • 1469-221X

Digital Object Identifier (DOI)

  • 10.1038/embor.2011.121

Language

  • eng