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CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism

BACKGROUND: Mitochondrial oxidative phosphorylation (OXPHOS) via the respiratory chain is required for the maintenance of tumour cell proliferation and regulation of epithelial to mesenchymal transition (EMT)-related phenotypes through mechanisms that are not fully understood. The essential mitochon...

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Autores principales: Thomas, Luke W., Esposito, Cinzia, Stephen, Jenna M., Costa, Ana S. H., Frezza, Christian, Blacker, Thomas S., Szabadkai, Gyorgy, Ashcroft, Margaret
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632184/
https://www.ncbi.nlm.nih.gov/pubmed/31346464
http://dx.doi.org/10.1186/s40170-019-0200-4
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author Thomas, Luke W.
Esposito, Cinzia
Stephen, Jenna M.
Costa, Ana S. H.
Frezza, Christian
Blacker, Thomas S.
Szabadkai, Gyorgy
Ashcroft, Margaret
author_facet Thomas, Luke W.
Esposito, Cinzia
Stephen, Jenna M.
Costa, Ana S. H.
Frezza, Christian
Blacker, Thomas S.
Szabadkai, Gyorgy
Ashcroft, Margaret
author_sort Thomas, Luke W.
collection PubMed
description BACKGROUND: Mitochondrial oxidative phosphorylation (OXPHOS) via the respiratory chain is required for the maintenance of tumour cell proliferation and regulation of epithelial to mesenchymal transition (EMT)-related phenotypes through mechanisms that are not fully understood. The essential mitochondrial import protein coiled-coil helix coiled-coil helix domain-containing protein 4 (CHCHD4) controls respiratory chain complex activity and oxygen consumption, and regulates the growth of tumours in vivo. In this study, we interrogate the importance of CHCHD4-regulated mitochondrial metabolism for tumour cell proliferation and EMT-related phenotypes, and elucidate key pathways involved. RESULTS: Using in silico analyses of 967 tumour cell lines, and tumours from different cancer patient cohorts, we show that CHCHD4 expression positively correlates with OXPHOS and proliferative pathways including the mTORC1 signalling pathway. We show that CHCHD4 expression significantly correlates with the doubling time of a range of tumour cell lines, and that CHCHD4-mediated tumour cell growth and mTORC1 signalling is coupled to respiratory chain complex I (CI) activity. Using global metabolomics analysis, we show that CHCHD4 regulates amino acid metabolism, and that CHCHD4-mediated tumour cell growth is dependent on glutamine. We show that CHCHD4-mediated tumour cell growth is linked to CI-regulated mTORC1 signalling and amino acid metabolism. Finally, we show that CHCHD4 expression in tumours is inversely correlated with EMT-related gene expression, and that increased CHCHD4 expression in tumour cells modulates EMT-related phenotypes. CONCLUSIONS: CHCHD4 drives tumour cell growth and activates mTORC1 signalling through its control of respiratory chain mediated metabolism and complex I biology, and also regulates EMT-related phenotypes of tumour cells. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40170-019-0200-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-66321842019-07-25 CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism Thomas, Luke W. Esposito, Cinzia Stephen, Jenna M. Costa, Ana S. H. Frezza, Christian Blacker, Thomas S. Szabadkai, Gyorgy Ashcroft, Margaret Cancer Metab Research BACKGROUND: Mitochondrial oxidative phosphorylation (OXPHOS) via the respiratory chain is required for the maintenance of tumour cell proliferation and regulation of epithelial to mesenchymal transition (EMT)-related phenotypes through mechanisms that are not fully understood. The essential mitochondrial import protein coiled-coil helix coiled-coil helix domain-containing protein 4 (CHCHD4) controls respiratory chain complex activity and oxygen consumption, and regulates the growth of tumours in vivo. In this study, we interrogate the importance of CHCHD4-regulated mitochondrial metabolism for tumour cell proliferation and EMT-related phenotypes, and elucidate key pathways involved. RESULTS: Using in silico analyses of 967 tumour cell lines, and tumours from different cancer patient cohorts, we show that CHCHD4 expression positively correlates with OXPHOS and proliferative pathways including the mTORC1 signalling pathway. We show that CHCHD4 expression significantly correlates with the doubling time of a range of tumour cell lines, and that CHCHD4-mediated tumour cell growth and mTORC1 signalling is coupled to respiratory chain complex I (CI) activity. Using global metabolomics analysis, we show that CHCHD4 regulates amino acid metabolism, and that CHCHD4-mediated tumour cell growth is dependent on glutamine. We show that CHCHD4-mediated tumour cell growth is linked to CI-regulated mTORC1 signalling and amino acid metabolism. Finally, we show that CHCHD4 expression in tumours is inversely correlated with EMT-related gene expression, and that increased CHCHD4 expression in tumour cells modulates EMT-related phenotypes. CONCLUSIONS: CHCHD4 drives tumour cell growth and activates mTORC1 signalling through its control of respiratory chain mediated metabolism and complex I biology, and also regulates EMT-related phenotypes of tumour cells. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40170-019-0200-4) contains supplementary material, which is available to authorized users. BioMed Central 2019-07-16 /pmc/articles/PMC6632184/ /pubmed/31346464 http://dx.doi.org/10.1186/s40170-019-0200-4 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Thomas, Luke W.
Esposito, Cinzia
Stephen, Jenna M.
Costa, Ana S. H.
Frezza, Christian
Blacker, Thomas S.
Szabadkai, Gyorgy
Ashcroft, Margaret
CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism
title CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism
title_full CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism
title_fullStr CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism
title_full_unstemmed CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism
title_short CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism
title_sort chchd4 regulates tumour proliferation and emt-related phenotypes, through respiratory chain-mediated metabolism
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632184/
https://www.ncbi.nlm.nih.gov/pubmed/31346464
http://dx.doi.org/10.1186/s40170-019-0200-4
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