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

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dc.creatorThomas, Luke W
dc.creatorEsposito, Cinzia
dc.creatorStephen, Jenna M
dc.creatorCosta, Ana SH
dc.creatorFrezza, Christian
dc.creatorBlacker, Thomas S
dc.creatorSzabadkai, Gyorgy
dc.creatorAshcroft, Margaret
dc.date2019-06-28T23:31:52Z
dc.date2019-06-28T23:31:52Z
dc.date2019
dc.date.accessioned2026-08-03T01:37:30Z
dc.descriptionBACKGROUND: 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.
dc.formatElectronic-eCollection
dc.formatapplication/pdf
dc.formatapplication/pdf
dc.identifier2049-3002
dc.identifierhttps://www.repository.cam.ac.uk/handle/1810/294210
dc.identifier10.17863/CAM.41310
dc.identifier2049-3002
dc.identifier.urihttps://repo.dare.co.zw/handle/123456789/156848
dc.languageeng
dc.languageeng
dc.publisherSpringer Nature
dc.publisherhttps://doi.org/10.1186/s40170-019-0200-4
dc.rightsAll rights reserved
dc.rightshttp://purl.org/NET/rdflicense/allrightsreserved
dc.subjectCoiled-coil helix coiled-coil helix domain-containing protein 4 (CHCHD4)
dc.subjectHIF-1α
dc.subjectcomplex I
dc.subjectdisulfide relay system
dc.subjecthypoxia
dc.subjectmitochondria
dc.subjectrespiratory chain
dc.subjecttumour growth
dc.subjecttumour metabolism
dc.titleCHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism.
dc.typeArticle

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