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SIRT3‐dependent deacetylation exacerbates acetaminophen hepatotoxicity

Zhongping Lu, Mohammed Bourdi, Jian H Li, Angel M Aponte, Yong Chen, David B Lombard, Marjan Gucek, Lance R Pohl, Michael N Sack

Author Affiliations

  1. Zhongping Lu1,
  2. Mohammed Bourdi2,
  3. Jian H Li1,
  4. Angel M Aponte3,
  5. Yong Chen3,
  6. David B Lombard4,
  7. Marjan Gucek3,
  8. Lance R Pohl2 and
  9. Michael N Sack (sackm{at}nhlbi.nih.gov)*,1
  1. 1 Center for Molecular Medicine, NHLBI, National Institutes of Health, Building 10‐CRC, Room 5‐3150, 10 Center Drive, Bethesda, Maryland, 20892, USA
  2. 2 Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, NHLBI, NIH, Building 10, Room 8N 110, Bethesda, Maryland, 20892, USA
  3. 3 Proteomic Core Facility, NHLBI, NIH, 10 Center Drive, Building 10, Room 8C103C, Bethesda, Maryland, 20892, USA
  4. 4 Department of Pathology and Institute of Gerontology, University of Michigan, 3015 BSRB, 109 Zina Pitcher Place, Ann Arbor, Michigan, 48109, USA
  1. * Tel: +1 301 402 9259; Fax: +1 301 402 0888; E‐mail: sackm{at}nhlbi.nih.gov

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.

  • Received January 24, 2011.
  • Revision received May 10, 2011.
  • Accepted May 25, 2011.