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

Abstract

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.

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

“…Mitochondrial oxidative phosphorylation (OXPHOS) via the respiratory chain is required by cancer cells for their proliferation. The mitochondrial import protein coiled-coil helix coiled-coil helix domain-containing protein (CHCHD4), which controls respiratory chain complex activity and oxygen consumption, promotes mTORC1 signaling and drives tumor cell growth [96]. mTORC1 also increases the expression of nucleus-encoded mitochondrial proteins via inhibition of 4EBP [97].…”

CHCHD4 (MIA40) and the mitochondrial disulfide relay system

“…Increased expression of CHCHD4 across a range of cancer types has been shown to correlate with OXPHOS and proliferative pathways including mTORC1 [ 28 , 85 , 86 ]. Consistently, overexpression of CHCHD4 in tumour cells was shown to increase both CI-activity and mTORC1 activation, as well as affecting glutamine metabolism [ 28 ].…”

“…Increased expression of CHCHD4 across a range of cancer types has been shown to correlate with OXPHOS and proliferative pathways including mTORC1 [ 28 , 85 , 86 ]. Consistently, overexpression of CHCHD4 in tumour cells was shown to increase both CI-activity and mTORC1 activation, as well as affecting glutamine metabolism [ 28 ]. Indeed, CHCHD4 overexpressing cells were shown to exhibit increased sensitivity to the growth-inhibiting effects of CI inhibitors [ 20 ], which could be rescued by either supplementation of cells with exogenous aspartate, or expression of a rotenone-insensitive yeast NADH-dehydrogenase (Ndi1) [ 28 ].…”

“…Studies have shown that dysregulation of the DRS underlies mitochondrial disease [ 23–27 ] and cancer [ 16 , 20 , 28–30 ]. Here, we summarise the recent advances made to our understanding of the role of CHCHD4 and the DRS in physiology and disease, with a specific focus on the emerging importance of CHCHD4 in regulating hypoxia signalling and metabolism in cancer.…”

Metabolic Constrains Rule Metastasis Progression

“…Together with carbohydrates and lipid metabolism, amino acid and, in particular, glutamine metabolism plays a key role in EMT [17]. Indeed, high intracellular glutamine levels were shown to be necessary to promote EMT in several in-vitro models [172]. In particular, efficient glutamine uptake via SLC1A5 transporter is fundamental for prostate cancer proliferation and metastasis via the upregulation of E2F-dependent cell cycle genes [173].…”