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  Decreased mitochondrial DNA content drives OXPHOS dysregulation in chromophobe renal cell carcinoma

Xiao, Y., Clima, R., Busch, J., Rabien, A., Kilic, E., Villegas, S. L., et al. (2020). Decreased mitochondrial DNA content drives OXPHOS dysregulation in chromophobe renal cell carcinoma. Cancer research: an official organ of the American Association for Cancer Research, CAN-20-0754. doi:10.1158/0008-5472.CAN-20-0754.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0006-C0B7-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0006-C0BA-F
Genre: Journal Article

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This work is part of the doctoral dissertation of Y.X.
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© 2020, American Association for Cancer Research
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 Creators:
Xiao, Yi1, Author              
Clima, Rosanna, Author
Busch, Jonas, Author
Rabien, Anja, Author
Kilic, Ergin, Author
Villegas, Sonia L. , Author
Timmermann, Bernd2, Author              
Attimonelli, Marcella , Author
Jung, Klaus, Author
Meierhofer, David1, Author              
Affiliations:
1Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479669              
2Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              

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Free keywords: Chromophobe renal cell carcinoma (chRCC); Renal oncocytoma (RO); oxidative phosphorylation (OXPHOS); mitochondrial DNA content; glutathione metabolism
 Abstract: Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma (RO) are closely related, rare kidney tumors. Mutations in complex I (CI)-encoding genes play an important role in dysfunction of the oxidative phosphorylation (OXPHOS) system in RO but are less frequently observed in chRCC. As such, the relevance of OXPHOS status and role of CI mutations in chRCC remain unknown. To address this issue, we performed proteome and metabolome profiling as well as mitochondrial whole-exome sequencing to detect mitochondrial alterations in chRCC tissue specimens. Multi-omic analysis revealed downregulation of electron transport chain (ETC) components in chRCC that differed from the expression profile in RO. A decrease in mitochondrial (mt)DNA content, rather than CI mutations, was the main cause for reduced OXPHOS in chRCC. There was a negative correlation between protein and transcript levels of nuclear DNA- but not mtDNA-encoded ETC complex subunits in chRCC. In addition, the reactive oxygen species scavenger glutathione (GSH) was upregulated in chRCC due to decreased expression of proteins involved in GSH degradation. These results demonstrate that distinct mechanisms of OXPHOS exist in chRCC and RO and that expression levels of ETC complex subunits can serve as a diagnostic marker for this rare malignancy.

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Language(s): eng - English
 Dates: 2020-07-162020-07-21
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1158/0008-5472.CAN-20-0754
 Degree: -

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Title: Cancer research : an official organ of the American Association for Cancer Research
  Other : Cancer Res.
Source Genre: Journal
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Publ. Info: Baltimore, Md. : Waverly Press
Pages: - Volume / Issue: - Sequence Number: CAN-20-0754 Start / End Page: - Identifier: ISSN: 0008-5472 (print)
ISSN: 1538-7445 (electronic)
CoNE: https://pure.mpg.de/cone/journals/resource/991042743115962