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The limited therapeutic effect of copper chelators and the early occurrence of mitochondrial deficits, however, undermine the prevalence of this mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We characterized mitochondrial DNA copy number and mutations as well as bioenergetic deficits in blood from patients with WD and in livers of tx\u2010j mice, a mouse model of hepatic copper accumulation. In vitro experiments with hepatocytes treated with CuSO<jats:sub>4<\/jats:sub> were conducted to validate in vivo studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Here, for the first time, we characterized the bioenergetic deficits in WD as consistent with a mitochondrial DNA depletion\u2010like 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\u2010j mouse model of WD. Tx\u2010j 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\u2010loaded HepG2 cells validated the concept of a direct copper\u2010mitochondrial DNA interaction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study underlines the relevance of targeting the copper\u2010mitochondrial DNA pool in the treatment of WD separate from the established copper\u2010induced oxidative stress\u2010mediated damage.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.14646","type":"journal-article","created":{"date-parts":[[2020,9,30]],"date-time":"2020-09-30T12:19:19Z","timestamp":1601468359000},"page":"2776-2787","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["mtDNA depletion\u2010like syndrome in Wilson disease"],"prefix":"10.1111","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5438-284X","authenticated-orcid":false,"given":"Valentina","family":"Medici","sequence":"first","affiliation":[{"name":"Department of Internal 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