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

Abstract

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 mitochondria. 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 liver tissue and compared the results with those in a series of healthy controls and patients without WD. FINDINGS: There was evidence of severe mitochondrial dysfunction in the livers of patients with WD. Enzyme activities were decreased as follows: complex 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, cholestasis, 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 accumulation, are important in WD pathogenesis. These results provide a rationale for a study of the use of antioxidants in WD.