SIRT3-dependent Deacetylation Exacerbates Acetaminophen Hepatotoxicity

EMBO Rep. 2011 Jul 1;12(8):840-6. doi: 10.1038/embor.2011.121.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Acetaminophen / toxicity*
  • Acetylation
  • Alanine Transaminase / blood
  • Aldehyde Dehydrogenase / metabolism
  • Aldehyde Dehydrogenase, Mitochondrial
  • Animals
  • Benzoquinones / metabolism
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / genetics*
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Imines / metabolism
  • Liver / drug effects
  • Liver / enzymology
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / enzymology
  • Mitochondria / metabolism
  • Mitochondrial Proteins / metabolism
  • Protein Binding
  • Sirtuin 3 / genetics*
  • Sirtuin 3 / metabolism*

Substances

  • Benzoquinones
  • Imines
  • Mitochondrial Proteins
  • Sirt3 protein, mouse
  • Acetaminophen
  • ALDH2 protein, mouse
  • Aldehyde Dehydrogenase
  • Aldehyde Dehydrogenase, Mitochondrial
  • Alanine Transaminase
  • Sirtuin 3
  • N-acetyl-4-benzoquinoneimine