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OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation

Rewiring of energy metabolism and adaptation of mitochondria are considered to impact on prostate cancer development and progression. Here, we report on mitochondrial respiration, DNA mutations and gene expression in paired benign/malignant human prostate tissue samples. Results reveal reduced respi...

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Autores principales: Schöpf, Bernd, Weissensteiner, Hansi, Schäfer, Georg, Fazzini, Federica, Charoentong, Pornpimol, Naschberger, Andreas, Rupp, Bernhard, Fendt, Liane, Bukur, Valesca, Giese, Irina, Sorn, Patrick, Sant’Anna-Silva, Ana Carolina, Iglesias-Gonzalez, Javier, Sahin, Ugur, Kronenberg, Florian, Gnaiger, Erich, Klocker, Helmut
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083862/
https://www.ncbi.nlm.nih.gov/pubmed/32198407
http://dx.doi.org/10.1038/s41467-020-15237-5
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author Schöpf, Bernd
Weissensteiner, Hansi
Schäfer, Georg
Fazzini, Federica
Charoentong, Pornpimol
Naschberger, Andreas
Rupp, Bernhard
Fendt, Liane
Bukur, Valesca
Giese, Irina
Sorn, Patrick
Sant’Anna-Silva, Ana Carolina
Iglesias-Gonzalez, Javier
Sahin, Ugur
Kronenberg, Florian
Gnaiger, Erich
Klocker, Helmut
author_facet Schöpf, Bernd
Weissensteiner, Hansi
Schäfer, Georg
Fazzini, Federica
Charoentong, Pornpimol
Naschberger, Andreas
Rupp, Bernhard
Fendt, Liane
Bukur, Valesca
Giese, Irina
Sorn, Patrick
Sant’Anna-Silva, Ana Carolina
Iglesias-Gonzalez, Javier
Sahin, Ugur
Kronenberg, Florian
Gnaiger, Erich
Klocker, Helmut
author_sort Schöpf, Bernd
collection PubMed
description Rewiring of energy metabolism and adaptation of mitochondria are considered to impact on prostate cancer development and progression. Here, we report on mitochondrial respiration, DNA mutations and gene expression in paired benign/malignant human prostate tissue samples. Results reveal reduced respiratory capacities with NADH-pathway substrates glutamate and malate in malignant tissue and a significant metabolic shift towards higher succinate oxidation, particularly in high-grade tumors. The load of potentially deleterious mitochondrial-DNA mutations is higher in tumors and associated with unfavorable risk factors. High levels of potentially deleterious mutations in mitochondrial Complex I-encoding genes are associated with a 70% reduction in NADH-pathway capacity and compensation by increased succinate-pathway capacity. Structural analyses of these mutations reveal amino acid alterations leading to potentially deleterious effects on Complex I, supporting a causal relationship. A metagene signature extracted from the transcriptome of tumor samples exhibiting a severe mitochondrial phenotype enables identification of tumors with shorter survival times.
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spelling pubmed-70838622020-03-23 OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation Schöpf, Bernd Weissensteiner, Hansi Schäfer, Georg Fazzini, Federica Charoentong, Pornpimol Naschberger, Andreas Rupp, Bernhard Fendt, Liane Bukur, Valesca Giese, Irina Sorn, Patrick Sant’Anna-Silva, Ana Carolina Iglesias-Gonzalez, Javier Sahin, Ugur Kronenberg, Florian Gnaiger, Erich Klocker, Helmut Nat Commun Article Rewiring of energy metabolism and adaptation of mitochondria are considered to impact on prostate cancer development and progression. Here, we report on mitochondrial respiration, DNA mutations and gene expression in paired benign/malignant human prostate tissue samples. Results reveal reduced respiratory capacities with NADH-pathway substrates glutamate and malate in malignant tissue and a significant metabolic shift towards higher succinate oxidation, particularly in high-grade tumors. The load of potentially deleterious mitochondrial-DNA mutations is higher in tumors and associated with unfavorable risk factors. High levels of potentially deleterious mutations in mitochondrial Complex I-encoding genes are associated with a 70% reduction in NADH-pathway capacity and compensation by increased succinate-pathway capacity. Structural analyses of these mutations reveal amino acid alterations leading to potentially deleterious effects on Complex I, supporting a causal relationship. A metagene signature extracted from the transcriptome of tumor samples exhibiting a severe mitochondrial phenotype enables identification of tumors with shorter survival times. Nature Publishing Group UK 2020-03-20 /pmc/articles/PMC7083862/ /pubmed/32198407 http://dx.doi.org/10.1038/s41467-020-15237-5 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Schöpf, Bernd
Weissensteiner, Hansi
Schäfer, Georg
Fazzini, Federica
Charoentong, Pornpimol
Naschberger, Andreas
Rupp, Bernhard
Fendt, Liane
Bukur, Valesca
Giese, Irina
Sorn, Patrick
Sant’Anna-Silva, Ana Carolina
Iglesias-Gonzalez, Javier
Sahin, Ugur
Kronenberg, Florian
Gnaiger, Erich
Klocker, Helmut
OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation
title OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation
title_full OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation
title_fullStr OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation
title_full_unstemmed OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation
title_short OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation
title_sort oxphos remodeling in high-grade prostate cancer involves mtdna mutations and increased succinate oxidation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083862/
https://www.ncbi.nlm.nih.gov/pubmed/32198407
http://dx.doi.org/10.1038/s41467-020-15237-5
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