학술논문

mtDNA depletion‐like syndrome in Wilson disease
Document Type
article
Source
Liver International. 40(11)
Subject
Medical Biochemistry and Metabolomics
Biomedical and Clinical Sciences
Neurodegenerative
Genetics
Digestive Diseases
Liver Disease
Chronic Liver Disease and Cirrhosis
Brain Disorders
Rare Diseases
Aetiology
2.1 Biological and endogenous factors
5.1 Pharmaceuticals
Development of treatments and therapeutic interventions
Animals
Copper
Copper-Transporting ATPases
DNA
Mitochondrial
Hepatolenticular Degeneration
Humans
Liver
Mice
Penicillamine
bioenergetics
copper
mitochondria
mitochondrial DNA
oxidative stress
penicillamine
Copper-transporting ATPases
Clinical Sciences
Gastroenterology & Hepatology
Clinical sciences
Language
Abstract
Background and aimsWilson disease (WD) is caused by mutations in the copper transporter ATP7B, with its main pathology attributed to copper-mediated oxidative damage. The limited therapeutic effect of copper chelators and the early occurrence of mitochondrial deficits, however, undermine the prevalence of this mechanism.MethodsWe characterized mitochondrial DNA copy number and mutations as well as bioenergetic deficits in blood from patients with WD and in livers of tx-j mice, a mouse model of hepatic copper accumulation. In vitro experiments with hepatocytes treated with CuSO4 were conducted to validate in vivo studies.ResultsHere, for the first time, we characterized the bioenergetic deficits in WD as consistent with a mitochondrial DNA depletion-like syndrome. This is evidenced by enriched DNA synthesis/replication pathways in serum metabolomics and decreased mitochondrial DNA copy number in blood of WD patients as well as decreased mitochondrial DNA copy number, increased citrate synthase activity, and selective Complex IV deficit in livers of the tx-j mouse model of WD. Tx-j mice treated with the copper chelator penicillamine, methyl donor choline or both ameliorated mitochondrial DNA damage but further decreased mitochondrial DNA copy number. Experiments with copper-loaded HepG2 cells validated the concept of a direct copper-mitochondrial DNA interaction.ConclusionsThis study underlines the relevance of targeting the copper-mitochondrial DNA pool in the treatment of WD separate from the established copper-induced oxidative stress-mediated damage.