NADH shuttling couples cytosolic reductive carboxylation of glutamine with glycolysis in cells with mitochondrial dysfunction

Gaude, E. et al. (2018) NADH shuttling couples cytosolic reductive carboxylation of glutamine with glycolysis in cells with mitochondrial dysfunction. Molecular Cell, 69(4), 581-593.e7. (doi: 10.1016/j.molcel.2018.01.034) (PMID:29452638) (PMCID:PMC5823973)

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The bioenergetics and molecular determinants of the metabolic response to mitochondrial dysfunction are incompletely understood, in part due to a lack of appropriate isogenic cellular models of primary mitochondrial defects. Here, we capitalize on a recently developed cell model with defined levels of m.8993T>G mutation heteroplasmy, mTUNE, to investigate the metabolic underpinnings of mitochondrial dysfunction. We found that impaired utilization of reduced nicotinamide adenine dinucleotide (NADH) by the mitochondrial respiratory chain leads to cytosolic reductive carboxylation of glutamine as a new mechanism for cytosol-confined NADH recycling supported by malate dehydrogenase 1 (MDH1). We also observed that increased glycolysis in cells with mitochondrial dysfunction is associated with increased cell migration in an MDH1-dependent fashion. Our results describe a novel link between glycolysis and mitochondrial dysfunction mediated by reductive carboxylation of glutamine.

Item Type:Articles
Additional Information:The work of E.G., C.S., and C.F. is supported by the Medical Research Council (MRC) Core Award to the MRC Cancer Unit (MC_UU_12022/7). E.G. thanks the MRC doctorate training (DTA studentship) for financial support. E.G. and C.F. thank Ana S.H. Costa for extensive support with mass spectrometry metabolomics. The work of A.D. was supported by the Q3 European Union Horizon 2020 grant SyMBioSys MSCA-ITN-2015-ETN #675585. Work of M.M. and P.A.G. was funded by the Medical Research Council, UK (MC_U105697135). T.B. and G.S. were funded by the Biochemical and Biophysical Research Council (grants BB/L020874/1 and BB/P018726/1) and the Wellcome Trust (097815/Z/11/Z). T.B. and G.S. thank Michael Duchen for helpful discussion. J.S.O. and S.P.C. were supported by the Medical Research Council (MC_UP_1201/4) and the Wellcome Trust (093734/Z/10/Z). We thank the laboratory of Costas Lyssiotis for sharing the constructs for targeting GOT1 and the laboratory of Eyal Gottlieb for sharing the Sdhb-deficient cells.
Glasgow Author(s) Enlighten ID:Gammage, Dr Payam
Authors: Gaude, E., Schmidt, C., Gammage, P. A., Dugourd, A., Blacker, T., Chew, S. P., Saez-Rodriguez, J., O'Neill, J. S., Szabadkai, G., Minczuk, M., and Frezza, C.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Molecular Cell
ISSN (Online):1097-4164
Published Online:15 February 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Molecular Cell 69(4):581-593.e7
Publisher Policy:Reproduced under a Creative Commons License

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