Liver mitochondrial membrane crosslinking and destruction in a rat model of Wilson disease

J Clin Invest. 2011 Apr;121(4):1508-18. doi: 10.1172/JCI45401.


Wilson disease (WD) is a rare hereditary condition that is caused by a genetic defect in the copper-transporting ATPase ATP7B that results in hepatic copper accumulation and lethal liver failure. The present study focuses on the structural mitochondrial alterations that precede clinical symptoms in the livers of rats lacking Atp7b, an animal model for WD. Liver mitochondria from these Atp7b–/– rats contained enlarged cristae and widened intermembrane spaces, which coincided with a massive mitochondrial accumulation of copper. These changes, however, preceded detectable deficits in oxidative phosphorylation and biochemical signs of oxidative damage, suggesting that the ultrastructural modifications were not the result of oxidative stress imposed by copper- dependent Fenton chemistry. In a cell-free system containing a reducing dithiol agent, isolated mitochondria exposed to copper underwent modifications that were closely related to those observed in vivo. In this cell-free system, copper induced thiol modifications of three abundant mitochondrial membrane proteins, and this correlated with reversible intramitochondrial membrane crosslinking, which was also observed in liver mitochondria from Atp7b–/– rats. In vivo, copper-chelating agents reversed mitochondrial accumulation of copper, as well as signs of intra-mitochondrial membrane crosslinking, thereby preserving the functional and structural integrity of mitochondria. Together, these findings suggest that the mitochondrion constitutes a pivotal target of copper in WD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / deficiency
  • Adenosine Triphosphatases / genetics
  • Animals
  • Cation Transport Proteins
  • Cell-Free System
  • Chelating Agents / pharmacology
  • Copper / metabolism
  • Copper-Transporting ATPases
  • Cross-Linking Reagents
  • Disease Models, Animal
  • Gene Knockout Techniques
  • Hepatolenticular Degeneration / genetics
  • Hepatolenticular Degeneration / metabolism
  • Hepatolenticular Degeneration / pathology*
  • Humans
  • In Vitro Techniques
  • Microscopy, Electron, Transmission
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / metabolism
  • Mitochondria, Liver / pathology*
  • Mitochondrial Proteins / metabolism
  • Rats
  • Sulfhydryl Compounds / metabolism


  • Cation Transport Proteins
  • Chelating Agents
  • Cross-Linking Reagents
  • Mitochondrial Proteins
  • Sulfhydryl Compounds
  • Copper
  • Adenosine Triphosphatases
  • Atp7b protein, rat
  • Copper-Transporting ATPases