Fragmentation of mitochondrial cardiolipin by copper ions in the Atp7b-/- mouse model of Wilson's disease

Chem Phys Lipids. 2011 Jul;164(5):393-400. doi: 10.1016/j.chemphyslip.2011.05.006. Epub 2011 May 30.


Cellular copper overload as found in Wilson's disease may disturb mitochondrial function and integrity. Atp7b(-/-) mice accumulate copper in the liver and serve as an animal model for this inherited disease. The molecular mechanism of copper toxicity in hepatocytes is poorly understood. Total mitochondrial lipids from liver of wild-type mice were subjected to oxidative stress by the Cu(2+)/H(2)O(2)/ascorbate system. Phosphatidic acid (PA) and phosphatidylhydroxyacetone (PHA) were detected as cardiolipin fragmentation products by thin-layer chromatography combined with MALDI-TOF mass spectrometry in oxidized samples, but not in unperturbed ones. The formation of PA and PHA in copper-treated model membrane correlated well with the decrease of cardiolipin. Mitochondrial lipids from Atp7b(-/-) mice of different age were analyzed for the presence of PA. While 32-weeks old wild-type (control) and Atp7b(-/-) mice did not show any PA, there was a steady increase in the amount of this lipid in Atp7b(-/-) mice in contrast to control with increasing age. Hepatocytes from elder Atp7b(-/-)mice contained morphologically changed mitochondria unlike cells from wild-type animals of the same age. We concluded that free-radical fragmentation of cardiolipin with the formation of PA is a likely mechanism that damages mitochondria under conditions of oxidative stress due to copper overload. Our findings are relevant for better understanding of molecular mechanisms for liver damage found in Wilson's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / deficiency
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Cardiolipins / metabolism*
  • Cation Transport Proteins / deficiency
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism*
  • Copper / metabolism*
  • Copper / toxicity
  • Copper-Transporting ATPases
  • Disease Models, Animal
  • Free Radicals / metabolism
  • Hepatolenticular Degeneration / metabolism*
  • Hepatolenticular Degeneration / pathology
  • Ions / chemistry
  • Liver / metabolism
  • Mice
  • Mice, Knockout
  • Mitochondria, Liver / metabolism*
  • Oxidative Stress
  • Phosphatidic Acids / metabolism


  • Atp7a protein, mouse
  • Cardiolipins
  • Cation Transport Proteins
  • Free Radicals
  • Ions
  • Phosphatidic Acids
  • Copper
  • Adenosine Triphosphatases
  • Copper-Transporting ATPases