TY - JOUR
T1 - MCT2 mediates concentration-dependent inhibition of glutamine metabolism by MOG
AU - Fets, Louise
AU - Driscoll, Paul C.
AU - Grimm, Fiona
AU - Jain, Aakriti
AU - Nunes, Patrícia M.
AU - Gounis, Michalis
AU - Doglioni, Ginevra
AU - Papageorgiou, George
AU - Ragan, Timothy J.
AU - Campos, Sebastien
AU - Silva dos Santos, Mariana
AU - MacRae, James I.
AU - O’Reilly, Nicola
AU - Wright, Alan J.
AU - Benes, Cyril H.
AU - Courtney, Kevin D.
AU - House, David
AU - Anastasiou, Dimitrios
N1 - Funding Information:
We thank all members of the laboratory of D.A. for valuable discussions and input throughout this work, particularly J. Macpherson and N. Bevan for technical help. We are grateful to L. Cantley for advice during early stages of this work. We acknowledge S. O’Callaghan (Bio21 Institute, University of Melbourne) for the algorithm to correct for natural isotope abundance in metabolomics data. We thank J. Kleinjung for advice with statistical methods, M. Howell for advice and help with cell proliferation and viability measurements, J. Cerveira for help with flow cytometry measurements and A. Gould for comments on the manuscript. We are grateful to the staff at the Medical Research Council National Biomedical NMR Centre at the Francis Crick Institute, where NMR data were obtained. This work was funded by the MRC (MC_UP_1202/1) and by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001033), the UK Medical Research Council (FC001033) and the Wellcome Trust (FC001033) to D.A.
Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - α-Ketoglutarate (αKG) is a key node in many important metabolic pathways. The αKG analog N-oxalylglycine (NOG) and its cell-permeable prodrug dimethyloxalylglycine (DMOG) are extensively used to inhibit αKG-dependent dioxygenases. However, whether NOG interference with other αKG-dependent processes contributes to its mode of action remains poorly understood. Here we show that, in aqueous solutions, DMOG is rapidly hydrolyzed, yielding methyloxalylglycine (MOG). MOG elicits cytotoxicity in a manner that depends on its transport by monocarboxylate transporter 2 (MCT2) and is associated with decreased glutamine-derived tricarboxylic acid–cycle flux, suppressed mitochondrial respiration and decreased ATP production. MCT2-facilitated entry of MOG into cells leads to sufficiently high concentrations of NOG to inhibit multiple enzymes in glutamine metabolism, including glutamate dehydrogenase. These findings reveal that MCT2 dictates the mode of action of NOG by determining its intracellular concentration and have important implications for the use of (D)MOG in studying αKG-dependent signaling and metabolism.
AB - α-Ketoglutarate (αKG) is a key node in many important metabolic pathways. The αKG analog N-oxalylglycine (NOG) and its cell-permeable prodrug dimethyloxalylglycine (DMOG) are extensively used to inhibit αKG-dependent dioxygenases. However, whether NOG interference with other αKG-dependent processes contributes to its mode of action remains poorly understood. Here we show that, in aqueous solutions, DMOG is rapidly hydrolyzed, yielding methyloxalylglycine (MOG). MOG elicits cytotoxicity in a manner that depends on its transport by monocarboxylate transporter 2 (MCT2) and is associated with decreased glutamine-derived tricarboxylic acid–cycle flux, suppressed mitochondrial respiration and decreased ATP production. MCT2-facilitated entry of MOG into cells leads to sufficiently high concentrations of NOG to inhibit multiple enzymes in glutamine metabolism, including glutamate dehydrogenase. These findings reveal that MCT2 dictates the mode of action of NOG by determining its intracellular concentration and have important implications for the use of (D)MOG in studying αKG-dependent signaling and metabolism.
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U2 - 10.1038/s41589-018-0136-y
DO - 10.1038/s41589-018-0136-y
M3 - Article
C2 - 30297875
AN - SCOPUS:85054578892
SN - 1552-4450
VL - 14
SP - 1032
EP - 1042
JO - Nature chemical biology
JF - Nature chemical biology
IS - 11
ER -