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Fontes, A. ; Pierson, H.* ; Bierła, J.B.* ; Eberhagen, C. ; Kinschel, J.* ; Akdogan, B. ; Rieder, T.* ; Sailer, J.* ; Reinold, Q.* ; Cielecka-Kuszyk, J.* ; Szymanska, S.* ; Neff, F.* ; Steiger, K.* ; Seelbach, O.* ; Zibert, A.* ; Schmidt, H.H.* ; Hauck, S.M. ; von Toerne, C. ; Michalke, B. ; Semrau, J.D.* ; DiSpirito, A.M.* ; Ramalho-Santos, J.* ; Kroemer, G.* ; Polishchuk, R.S.* ; Azul, A.M.* ; DiSpirito, A.* ; Socha, P.* ; Lutsenko, S.* ; Zischka, H.

Copper impairs the intestinal barrier integrity in Wilson disease.

Metabolism 158:155973 (2024)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Copper ; Intestine ; Methanobactin ; Mitochondria ; Wilson Disease; Inflammatory-bowel-disease; Ulcerative-colitis; Zinc; Ceruloplasmin; Epidemiology; Transporter; Atp7b; Model; Iron

ISSN (print) / ISBN 0026-0495

e-ISSN 1532-8600

Journal Metabolism: clinical and experimental

Quellenangaben Volume: 158, Article Number: 155973

Publisher Elsevier

Publishing Place 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Molecular Toxicology and Pharmacology (TOXI)
CF Metabolomics & Proteomics (CF-MPC)
Research Unit Analytical BioGeoChemistry (BGC)

Grants Deutsche Forschungsgemeinschaft (DFG)
Bundesministerium fr Bildung und Forschung (BMBF)
National Institute of Health
FCT- Fundacao para a Ciencia e a Tecnologia
European Union
The mtFOIE GRAS projects
FOIE GRAS