Abstract
BackgroundMitochondrial 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.ResultsUsing 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.ConclusionsCHCHD4 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.
Highlights
Dividing tumour cells require specific metabolites to support proliferation, and the metabolic rewiring of malignant cells contributes both to transformation and tumour progression [1]
Using gene set enrichment analysis (GSEA) to identify key tumour-related pathways associated with CHCHD4 expression that are linked to OXPHOS and tumour proliferation, we investigate the role of CHCHD4 in regulating tumour cell growth, mTORC1 signalling, amino acid metabolism and EMTrelated phenotypes
To better understand the relationship between CHCHD4 and tumour cell proliferation, we carried out GSEA on genes that were significantly correlated with CHCHD4 expression in transcriptomic data from a panel of 967 tumour cell lines (Novartis/Broad Institute Tumour Cell Line Encyclopaedia)
Summary
Dividing tumour cells require specific metabolites to support proliferation, and the metabolic rewiring of malignant cells contributes both to transformation and tumour progression [1]. Mitochondria support cellular proliferation by supplying ATP for the bioenergetic demands of the cell through OXPHOS, and are the site of reactions which supply the cell with precursors for the synthesis of macromolecules such as DNA, proteins and lipids [17]. Depletion of mitochondrial DNA in tumour cells (ρ0 cells) inhibits tumour cell proliferation and tumorigenesis in vitro and in vivo, demonstrating the importance of mitochondria in a cancer setting [19,20,21]. 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. We interrogate the importance of CHCHD4-regulated mitochondrial metabolism for tumour cell proliferation and EMT-related phenotypes, and elucidate key pathways involved
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