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Mol Cell. 2018 Feb 15;69(4):581-593.e7. doi: 10.1016/j.molcel.2018.01.034.

NADH Shuttling Couples Cytosolic Reductive Carboxylation of Glutamine with Glycolysis in Cells with Mitochondrial Dysfunction.

Author information

1
Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
2
Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK.
3
Joint Research Centre for Computational Biomedicine, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany.
4
Research Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
5
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 2QH, UK.
6
Joint Research Centre for Computational Biomedicine, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK.
7
Research Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK; Department of Biomedical Sciences, University of Padua and CNR Neuroscience Institute, Padua 35121, Italy; The Francis Crick Institute, Midland Road, London NW1 1AT, UK.
8
Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK. Electronic address: cf366@mrc-cu.cam.ac.uk.

Abstract

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.

KEYWORDS:

GAPDH; MDH1; NADH; cancer metabolism; cell migration; glycolysis; malate-aspartate shuttle; mitochondrial dysfunction; mitochondrial metabolism; reductive carboxylation

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