Gaude, Edoardo Schmidt, Christina Gammage, Payam A Dugourd, Aurelien Blacker, Thomas Chew, Sew Peak Saez-Rodriguez, Julio O'Neill, John S Szabadkai, Gyorgy Minczuk, Michal Frezza, Christian NADH shuttling couples cytosolic reductive carboxylation of glutamine with glycolysis in cells with mitochondrial dysfunction 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. GAPDH;MDH1;NADH;cancer metabolism;cell migration;glycolysis;malate-aspartate shuttle;mitochondrial dysfunction;mitochondrial metabolism;reductive carboxylation;Bone Neoplasms;Cell Movement;Citric Acid Cycle;Cytosol;DNA, Mitochondrial;Energy Metabolism;Female;Glucose;Glutamine;Glycolysis;Humans;Malate Dehydrogenase;Mitochondria;NAD;Osteosarcoma;Oxidation-Reduction;Tumor Cells, Cultured;Szabadkai - Sat;06 Biological Sciences;11 Medical and Health Sciences;Developmental Biology 2020-07-17
    https://crick.figshare.com/articles/journal_contribution/NADH_shuttling_couples_cytosolic_reductive_carboxylation_of_glutamine_with_glycolysis_in_cells_with_mitochondrial_dysfunction/12661436