Author information
1Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; DCV-Department of Life Sciences, Faculty of Sciences and Technology of the University of Coimbra, Coimbra, Portugal.
2Department of Physiology, Johns Hopkins Medical Institutes, Baltimore, MD, USA.
3Department of Pathomorphology, Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland.
4Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
5Technical University Munich, Institute of Toxicology and Environmental Hygiene, Munich, Germany.
6Munich Clinic Harlaching, Munich, Germany.
7Comparative Experimental Pathology Department, Institute for General Pathology and Pathological Anatomy, Technical University of Munich (TUM), Germany.
8Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany.
9Research Unit Protein Science, Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Munich, Germany.
10Research Unit Analytical BioGeoChemistry, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
11Department of Civil and Environmental Engineering, University of Michigan, Ann Arbor, MI, 48109-2125, USA.
12Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, USA.
13CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; DCV-Department of Life Sciences, Faculty of Sciences and Technology of the University of Coimbra, Coimbra, Portugal; CIBB-Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.
14Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France; Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-, HP, Paris, France.
15Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy.
16CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; CIBB-Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal; IIIUC-Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
17Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730 Warsaw, Poland.
18Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany; Technical University Munich, Institute of Toxicology and Environmental Hygiene, Munich, Germany. Electronic address: hans.zischka@helmholtz-munich.de.
Abstract
In Wilson disease (WD), liver copper (Cu) excess, caused by mutations in the ATPase Cu transporting beta (ATP7B), has been extensively studied. In contrast, in the gastrointestinal tract, responsible for dietary Cu uptake, ATP7B malfunction is poorly explored. We therefore investigated gut biopsies from WD patients and compared intestines from two rodent WD models and from human ATP7B knock-out intestinal cells to their respective wild-type controls. We observed gastrointestinal (GI) inflammation in patients, rats and mice lacking ATP7B. Mitochondrial alterations and increased intestinal leakage were observed in WD rats, Atp7b-/- mice and human ATP7B KO Caco-2 cells. Proteome analyses of intestinal WD homogenates revealed profound alterations of energy and lipid metabolism. The intestinal damage in WD animals and human ATP7B KO cells did not correlate with absolute Cu elevations, but likely reflects intracellular Cu mislocalization. Importantly, Cu depletion by the high-affinity Cu chelator methanobactin (MB) restored enterocyte mitochondria, epithelial integrity, and resolved gut inflammation in WD rats and human WD enterocytes, plausibly via autophagy-related mechanisms. Thus, we report here before largely unrecognized intestinal damage in WD, occurring early on and comprising metabolic and structural tissue damage, mitochondrial dysfunction, and compromised intestinal barrier integrity and inflammation, that can be resolved by high-affinity Cu chelation treatment.