| Liver mitochondrial membrane crosslinking and destruction in a rat model of Wilson disease. | |
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MedLine Citation:
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PMID: 21364284 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Wilson disease (WD) is a rare hereditary condition that is caused by a genetic defect in the copper-transporting ATPase ATP7B that results in hepatic copper accumulation and lethal liver failure. The present study focuses on the structural mitochondrial alterations that precede clinical symptoms in the livers of rats lacking Atp7b, an animal model for WD. Liver mitochondria from these Atp7b–/– rats contained enlarged cristae and widened intermembrane spaces, which coincided with a massive mitochondrial accumulation of copper. These changes, however, preceded detectable deficits in oxidative phosphorylation and biochemical signs of oxidative damage, suggesting that the ultrastructural modifications were not the result of oxidative stress imposed by copper- dependent Fenton chemistry. In a cell-free system containing a reducing dithiol agent, isolated mitochondria exposed to copper underwent modifications that were closely related to those observed in vivo. In this cell-free system, copper induced thiol modifications of three abundant mitochondrial membrane proteins, and this correlated with reversible intramitochondrial membrane crosslinking, which was also observed in liver mitochondria from Atp7b–/– rats. In vivo, copper-chelating agents reversed mitochondrial accumulation of copper, as well as signs of intra-mitochondrial membrane crosslinking, thereby preserving the functional and structural integrity of mitochondria. Together, these findings suggest that the mitochondrion constitutes a pivotal target of copper in WD. |
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Authors:
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Hans Zischka; Josef Lichtmannegger; Sabine Schmitt; Nora Jägemann; Sabine Schulz; Daniela Wartini; Luise Jennen; Christian Rust; Nathanael Larochette; Lorenzo Galluzzi; Veronique Chajes; Nathan Bandow; Valérie S Gilles; Alan A DiSpirito; Irene Esposito; Martin Goettlicher; Karl H Summer; Guido Kroemer |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 121 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-05-31 Completed Date: 2011-06-21 Revised Date: 2012-02-07 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 1508-18 Citation Subset: AIM; IM |
Affiliation:
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Institute of Toxicology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany. zischka@helmholtz-muenchen.de |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphatases
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deficiency,
genetics Animals Cation Transport Proteins Cell-Free System Chelating Agents / pharmacology Copper / metabolism Cross-Linking Reagents Disease Models, Animal Gene Knockout Techniques Hepatolenticular Degeneration / genetics, metabolism, pathology* Humans Microscopy, Electron, Transmission Mitochondria, Liver / drug effects, metabolism, pathology* Mitochondrial Proteins / metabolism Rats Sulfhydryl Compounds / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Cation Transport Proteins; 0/Chelating Agents; 0/Cross-Linking Reagents; 0/Mitochondrial Proteins; 0/Sulfhydryl Compounds; 7440-50-8/Copper; EC 3.6.1.-/Adenosine Triphosphatases; EC 3.6.3.4/Atp7b protein, rat |
| Comments/Corrections | |
Comment In:
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Hepatology. 2011 Jul;54(1):358-60
[PMID:
21710473
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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