Valentina Medici1, Gaurav V Sarode1, Eleonora Napoli2, Gyu-Young Song2, Noreene M Shibata1, Andre O Guimarães2,3, Charles E Mordaunt4,5, Dorothy A Kieffer1, Tagreed A Mazi6,7, Anna Czlonkowska8, Tomasz Litwin8, Janine M LaSalle4,5, Cecilia Giulivi2,5. 1. Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA. 2. Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA. 3. Laboratório de Ciências Físicas, Universidade Estadual do Norte Fluminense, Campos dos Goytacazes RJ, Brazil. 4. Department of Medical Microbiology and Immunology, Genome Center, University of California Davis, Davis, CA, USA. 5. Medical Investigations of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, Davis, CA, USA. 6. Department of Nutrition, University of California Davis, Davis, CA, USA. 7. Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia. 8. Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.
Abstract
BACKGROUND AND AIMS: Wilson 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. METHODS: We 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. RESULTS: Here, 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. CONCLUSIONS: This 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.
BACKGROUND AND AIMS: Wilson 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. METHODS: We 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. RESULTS: Here, 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 WDpatients 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. CONCLUSIONS: This 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.
Authors: Timothy R Koves; John R Ussher; Robert C Noland; Dorothy Slentz; Merrie Mosedale; Olga Ilkayeva; James Bain; Robert Stevens; Jason R B Dyck; Christopher B Newgard; Gary D Lopaschuk; Deborah M Muoio Journal: Cell Metab Date: 2008-01 Impact factor: 27.287
Authors: Gaurav V Sarode; Kyoungmi Kim; Dorothy A Kieffer; Noreene M Shibata; Tomas Litwin; Anna Czlonkowska; Valentina Medici Journal: Metabolomics Date: 2019-03-12 Impact factor: 4.290