Toxicity of copper on isolated liver mitochondria: impairment at complexes I, II, and IV leads to increased ROS production

Cell Biochem Biophys. 2014 Sep;70(1):367-81. doi: 10.1007/s12013-014-9922-7.


Oxidative damage has been implicated in disorders associated with abnormal copper metabolism and also Cu(2+) overloading states. Besides, mitochondria are one of the most important targets for Cu(2+), an essential redox transition metal, induced hepatotoxicity. In this study, we aimed to investigate the mitochondrial toxicity mechanisms on isolated rat liver mitochondria. Rat liver mitochondria in both in vivo and in vitro experiments were obtained by differential ultracentrifugation and the isolated liver mitochondria were then incubated with different concentrations of Cu(2+). Our results showed that Cu(2+) induced a concentration and time-dependent rise in mitochondrial ROS formation, lipid peroxidation, and mitochondrial membrane potential collapse before mitochondrial swelling ensued. Increased disturbance in oxidative phosphorylation was also shown by decreased ATP concentration and decreased ATP/ADP ratio in Cu(2+)-treated isolated mitochondria. In addition, collapse of mitochondrial membrane potential (MMP), mitochondrial swelling, and release of cytochrome c following of Cu(2+) treatment were well inhibited by pretreatment of mitochondria with CsA and BHT. Our results showed that Cu(2+) could interact with respiratory complexes (I, II, and IV). This suggests that Cu(2+)-induced liver toxicity is the result of metal's disruptive effect on liver hepatocyte mitochondrial respiratory chain that is the obvious cause of Cu(2+)-induced ROS formation, lipid peroxidation, mitochondrial membrane potential decline, and cytochrome c expulsion which start cell death signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Animals
  • Biomarkers / blood
  • Copper / toxicity*
  • Cytochromes / metabolism
  • Electron Transport Chain Complex Proteins / metabolism*
  • Electron Transport Complex I / metabolism
  • Electron Transport Complex II / metabolism
  • Electron Transport Complex IV / metabolism
  • Glutathione / metabolism
  • Lipid Peroxidation / drug effects
  • Liver / cytology
  • Liver / drug effects
  • Liver / metabolism
  • Liver / physiology
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria, Liver / drug effects*
  • Mitochondria, Liver / enzymology
  • Mitochondria, Liver / metabolism*
  • Mitochondrial Swelling / drug effects
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism*


  • Biomarkers
  • Cytochromes
  • Electron Transport Chain Complex Proteins
  • Reactive Oxygen Species
  • Adenosine Diphosphate
  • Copper
  • Adenosine Triphosphate
  • Electron Transport Complex II
  • Electron Transport Complex IV
  • Electron Transport Complex I
  • Glutathione