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  Loss of complex I due to mitochondrial DNA mutations in renal oncocytoma

Mayr, J. A., Meierhofer, D., Zimmermann, F., Feichtinger, R., Kögler, C., Ratschek, M., et al. (2008). Loss of complex I due to mitochondrial DNA mutations in renal oncocytoma. Clinical Cancer Research, 14(8), 2270-2275. doi:10.1158/1078-0432.CCR-07-4131.

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© 2008 American Association for Cancer Research
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 Creators:
Mayr, Johannes A.1, Author
Meierhofer, David1, 2, Author           
Zimmermann, Franz1, Author
Feichtinger, Rene1, Author
Kögler, Christian, Author
Ratschek, Manfred, Author
Schmeller, Nikolaus, Author
Sperl, Wolfgang1, Author
Kofler, Barbara1, Author
Affiliations:
1Departments of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria, ou_persistent22              
2Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479669              

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Free keywords: oncocytoma, complex I, respiratory chain, mitochondrial DNA
 Abstract: Purpose: Many solid tumors exhibit abnormal aerobic metabolism characterized by increased glycolytic capacity and decreased cellular respiration. Recently, mutations in the nuclear encoded mitochondrial enzymes fumarate hydratase and succinate dehydrogenase have been identified in certain tumor types, thus demonstrating a direct link between mitochondrial energy metabolism and tumorigenesis. Although mutations in the mitochondrial genome (mitochondrial DNA, mtDNA) also can affect aerobic metabolism and mtDNA alterations are frequently observed in tumor cells, evidence linking respiratory chain deficiency in a specific tumor type to a specific mtDNA mutation has been lacking. Experimental Design: To identify mitochondrial alterations in oncocytomas, we investigated the activities of respiratory chain enzymes and sequenced mtDNA in 15 renal oncocytoma tissues. Results: Here, we show that loss of respiratory chain complex I (NADH/ubiquinone oxidoreductase) is associated with renal oncocytoma. Enzymatic activity of complex I was undetectable or greatly reduced in the tumor samples (n = 15). Blue Native gel electrophoresis of the multisubunit enzyme complex revealed a lack of assembled complex I. Mutation analysis of the mtDNA showed frame-shift mutations in the genes of either subunit ND1, ND4, or ND5 of complex I in 9 of the 15 tumors. Conclusion: Our data indicate that isolated loss of complex I is a specific feature of renal oncocytoma and that this deficiency is frequently caused by somatic mtDNA mutations.

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Language(s): eng - English
 Dates: 2008-04-15
 Publication Status: Issued
 Pages: -
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 Rev. Type: -
 Identifiers: DOI: 10.1158/1078-0432.CCR-07-4131
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Title: Clinical Cancer Research
  Other : Clin. Cancer Res.
Source Genre: Journal
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Publ. Info: Denville, NJ : Association for Cancer Research
Pages: - Volume / Issue: 14 (8) Sequence Number: - Start / End Page: 2270 - 2275 Identifier: ISSN: 1078-0432
CoNE: https://pure.mpg.de/cone/journals/resource/954925605818