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

• Published in: The Lancet (British edition) 2000-08, Vol.356 (9228), p.469-474
• Main Authors: Gu, M, Cooper, JM, Butler, P, Walker, AP, Mistry, PK, Dooley, JS, Schapira, AHV
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Antioxidants; Biological and medical sciences; Child; Copper; Copper - metabolism; Disease; DNA Mutational Analysis; Enzymatic activity; Female; Hepatolenticular Degeneration - enzymology; Hepatolenticular Degeneration - metabolism; Humans; Liver; Liver - metabolism; Male; Medical sciences; Metabolic diseases; Metals (hemochromatosis...); Middle Aged; Mitochondria, Liver - metabolism; Other metabolic disorders; Oxidative Phosphorylation
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(00)02556-3

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. 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. 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. 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.