Methanobactin reverses acute liver failure in a rat model of Wilson disease.
In Wilson disease (WD), functional loss of ATPase copper-transporting β (ATP7B) impairs biliary copper excretion, leading to excessive copper accumulation in the liver and fulminant hepatitis. Current US Food and Drug Administration- and European Medicines Agency-approved pharmacological treatments usually fail to restore copper homeostasis in patients with WD who have progressed to acute liver failure, leaving liver transplantation as the only viable treatment option. Here, we investigated the therapeutic utility of methanobactin (MB), a peptide produced by Methylosinus trichosporium OB3b, which has an exceptionally high affinity for copper. We demonstrated that ATP7B-deficient rats recapitulate WD-associated phenotypes, including hepatic copper accumulation, liver damage, and mitochondrial impairment. Short-term treatment of these rats with MB efficiently reversed mitochondrial impairment and liver damage in the acute stages of liver copper accumulation compared with that seen in untreated ATP7B-deficient rats. This beneficial effect was associated with depletion of copper from hepatocyte mitochondria. Moreover, MB treatment prevented hepatocyte death, subsequent liver failure, and death in the rodent model. These results suggest that MB has potential as a therapeutic agent for the treatment of acute WD.
Josef
J
Lichtmannegger
Christin
C
Leitzinger
Ralf
R
Wimmer
Sabine
S
Schmitt
Sabine
S
Schulz
Yaschar
Y
Kabiri
Carola
C
Eberhagen
Tamara
T
Rieder
Dirk
D
Janik
Frauke
F
Neff
Beate K
BK
Straub
Peter
P
Schirmacher
Alan A
AA
DiSpirito
Nathan
N
Bandow
Bipin S
BS
Baral
Andrew
A
Flatley
Elisabeth
E
Kremmer
Gerald
G
Denk
Florian P
FP
Reiter
Simon
S
Hohenester
Friedericke
F
Eckardt-Schupp
Norbert A
NA
Dencher
Jerzy
J
Adamski
Vanessa
V
Sauer
Christoph
C
Niemietz
Hartmut H J
HH
Schmidt
Uta
U
Merle
Daniel Nils
DN
Gotthardt
Guido
G
Kroemer
Karl Heinz
KH
Weiss
Hans
H
Zischka
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000737:chemistry; D027682:Cation Transport Proteins / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry; D003300:Copper / Q000737:chemistry; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000378:metabolism; D006527:Hepatolenticular Degeneration / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects; D017114:Liver Failure, Acute / Q000188:drug therapy*; D008928:Mitochondria / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D010641:Phenotype; D051381:Rats
D027682:Cation Transport Proteins; D002614:Chelating Agents; D007093:Imidazoles; D009842:Oligopeptides; C491147:methanobactin; D003300:Copper; D000251:Adenosine Triphosphatases; C550619:Atp7b protein, rat; D000073840:Copper-Transporting ATPases