Fontes, Adriana; Pierson, Hannah; Bierła, Joanna B; Eberhagen, Carola; Kinschel, Jennifer; Akdogan, Banu; Rieder, Tamara; Sailer, Judith; Reinold, Quirin; Cielecka-Kuszyk, Joanna; Szymańska, Sylwia; Neff, Frauke; Steiger, Katja; Seelbach, Olga; Zibert, Andree; Schmidt, Hartmut H; Hauck, Stefanie M; von Toerne, Christine; Michalke, Bernhard; Semrau, Jeremy D; DiSpirito, Ana M; Ramalho-Santos, João; Kroemer, Guido; Polishchuk, Roman; Azul, Anabela Marisa; DiSpirito, Alan; Socha, Piotr; Lutsenko, Svetlana; Zischka, Hans     «

Fontes, Adriana; Pierson, Hannah; Bierła, Joanna B; Eberhagen, Carola; Kinschel, Jennifer; Akdogan, Banu; Rieder, Tamara; Sailer, Judith; Reinold, Quirin; Cielecka-Kuszyk, Joanna; Szymańska, Sylwia; Neff, Frauke; Steiger, Katja; Seelbach, Olga; Zibert, Andree; Schmidt, Hartmut H; Hauck, Stefanie M; von Toerne, Christine; Michalke, Bernhard; Semrau, Jeremy D; DiSpirito, Ana M; Ramalho-Santos, João; Kroemer, Guido; Polishchuk, Roman; Azul, Anabela Marisa; DiSpirito, Alan; Socha, Piotr; Lutsenko, S...     »

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.      «

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) inflammatio...     »