NADH shuttling couples cytosolic reductive carboxylation of glutamine with glycolysis in cells with mitochondrial dysfunction
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Edoardo Gaude Christina Schmidt Payam A Gammage Aurelien Dugourd Thomas Blacker Sew Peak Chew Julio Saez-Rodriguez John S O'Neill Gyorgy Szabadkai Michal Minczuk Christian FrezzaAbstract
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.
Journal details
Journal Molecular Cell
Volume 69
Issue number 4
Pages 581-593.e7
Available online
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Publisher website (DOI) 10.1016/j.molcel.2018.01.034
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Europe PubMed Central 29452638
Pubmed 29452638
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