Oxidative-phosphorylation defects in liver of patients with Wilson's disease

Background Wilson's disease (WD) is caused by mutations in a P-type ATPase and is associated with copper deposition in liver and brain. The WD protein is present in the trans-Golgi network and may also be imported into mitoch ondria. The WD protein functions as a P-type copper transporting ATPase in the Golgi but any action in mitochondria is at present unknown. Methods We studied mitochondrial function and aconitase activity in WD live r tissue and compared the results with those in a series of healthy control s and patients without WD. Findings There was evidence of severe mitochondrial dysfunction in the live rs of patients with WD. Enzyme activities were decreased as follows: comple x I by 62%, complex II+III by 52%, complex IV by 33%, and aconitase by 71%. These defects did not seem to be secondary to penicillamine use, cholestas is, or poor hepatocellular synthetic function, Interpretation The results show that there is a defect of energy metabolism in WD. The pattern of enzyme defects suggests that free-radical formation and oxidative damage, probably mediated via mitochondrial copper accumulati on, are important in WD pathogenesis, These results provide a rationale for a study of the use of antioxidants in WD.