title: A novel effect of DMOG on cell metabolism: direct inhibition of mitochondrial function precedes HIF target gene expression.
abstract: Abnormal accumulation of oncometabolite fumarate and succinate is associated with inhibition of mitochondrial function and carcinogenesis. By competing with α-ketoglutarate, oncometabolites also activate hypoxia inducible factors (HIFs), which makes oncometabolite mimetics broadly utilised in hypoxia research. We found that dimethyloxalylglycine (DMOG), a synthetic analogue of α-ketoglutarate, commonly used to induce HIF signalling, inhibits O2 consumption in cancer cell lines HCT116 and PC12, well before activation of HIF pathways. A rapid suppression of cellular respiration was accompanied by a decrease in histone H4 lysine 16 acetylation and not abolished by double knockdown of HIF-1α and HIF-2α. In agreement with this, production of NADH and state 3 respiration in isolated mitochondria were down-regulated by the de-esterified DMOG derivative, N-oxalylglycine. Exploring the roles of DMOG as a putative inhibitor of glutamine/α-ketoglutarate metabolic axis, we found that the observed suppression of OxPhos and compensatory activation of glycolytic ATP flux make cancer cells vulnerable to combined treatment with DMOG and inhibitors of glycolysis. On the other hand, DMOG treatment impairs deep cell deoxygenation in 3D tissue culture models, demonstrating a potential to relieve functional stress imposed by deep hypoxia on tumour, ischemic or inflamed tissues. Indeed, using a murine model of colitis, we found that O2 availability in the inflamed colon tissue rapidly increased after application of DMOG, which could contribute to the known therapeutic effect of this compound. Overall, our results provide new insights into the relationship between mitochondrial function, O2 availability, metabolic reprogramming and associated diseases.
authors.affiliation: School of Biochemistry & Cell Biology, University College Cork, Cork, Ireland. Electronic address: a.zhdanov@ucc.ie.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Zhdanov
authors.affiliation: School of Biochemistry & Cell Biology, University College Cork, Cork, Ireland.
authors.forename: Irina A
authors.initials: IA
authors.lastname: Okkelman
authors.affiliation: School of Biochemistry & Cell Biology, University College Cork, Cork, Ireland.
authors.forename: Fergus W J
authors.initials: FW
authors.lastname: Collins
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Melgar
authors.affiliation: School of Biochemistry & Cell Biology, University College Cork, Cork, Ireland.
authors.forename: Dmitri B
authors.initials: DB
authors.lastname: Papkovsky
keywords: DMOG; Energy stress; Inflammation; Mitochondrial respiration; Oncometabolite; Tissue O(2) imaging