mtDNA depletion-like syndrome in Wilson disease.

Autor:	Medici V; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA., Sarode GV; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA., Napoli E; Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA., Song GY; Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA., Shibata NM; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA., Guimarães AO; Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA.; Laboratório de Ciências Físicas, Universidade Estadual do Norte Fluminense, Campos dos Goytacazes RJ, Brazil., Mordaunt CE; Department of Medical Microbiology and Immunology, Genome Center, University of California Davis, Davis, CA, USA.; Medical Investigations of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, Davis, CA, USA., Kieffer DA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA., Mazi TA; Department of Nutrition, University of California Davis, Davis, CA, USA.; Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia., Czlonkowska A; Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland., Litwin T; Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland., LaSalle JM; Department of Medical Microbiology and Immunology, Genome Center, University of California Davis, Davis, CA, USA.; Medical Investigations of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, Davis, CA, USA., Giulivi C; Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA.; Medical Investigations of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, Davis, CA, USA.
Jazyk:	angličtina
Zdroj:	Liver international : official journal of the International Association for the Study of the Liver [Liver Int] 2020 Nov; Vol. 40 (11), pp. 2776-2787. Date of Electronic Publication: 2020 Sep 30.
DOI:	10.1111/liv.14646
Abstrakt:	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 CuSO 4 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. (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
Databáze:	MEDLINE
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