NADH Shuttling Couples Cytosolic Reductive Carboxylation of Glutamine with Glycolysis in Cells with Mitochondrial Dysfunction.
Authors
Gaude, Edoardo
Schmidt, Christina
Gammage, Payam A
Dugourd, Aurelien
Blacker, Thomas
Chew, Sew Peak
Saez-Rodriguez, Julio
Szabadkai, Gyorgy
Publication Date
2018-02-15Journal Title
Mol Cell
ISSN
1097-2765
Publisher
Elsevier BV
Volume
69
Issue
4
Pages
581-593.e7
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print
Metadata
Show full item recordCitation
Gaude, E., Schmidt, C., Gammage, P. A., Dugourd, A., Blacker, T., Chew, S. P., Saez-Rodriguez, J., et al. (2018). NADH Shuttling Couples Cytosolic Reductive Carboxylation of Glutamine with Glycolysis in Cells with Mitochondrial Dysfunction.. Mol Cell, 69 (4), 581-593.e7. https://doi.org/10.1016/j.molcel.2018.01.034
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
Tumor Cells, Cultured, Mitochondria, Cytosol, Humans, Osteosarcoma, Bone Neoplasms, NAD, Malate Dehydrogenase, Glucose, Glutamine, DNA, Mitochondrial, Cell Movement, Citric Acid Cycle, Energy Metabolism, Oxidation-Reduction, Glycolysis, Female
Sponsorship
MRC (unknown)
Medical Research Council (MC_U105697135)
Medical Research Council (MC_UU_00015/4)
Medical Research Council (MC_UU_12022/7)
Wellcome Trust (093734/Z/10/Z)
Medical Research Council (MC_UU_12022/6)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1016/j.molcel.2018.01.034
This record's URL: https://www.repository.cam.ac.uk/handle/1810/274585
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