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

TitleNADH Shuttling Couples Cytosolic Reductive Carboxylation of Glutamine with Glycolysis in Cells with Mitochondrial Dysfunction.
Publication TypeJournal Article
Year of Publication2018
AuthorsGaude, E, Schmidt, C, Gammage, PA, Dugourd, A, Blacker, T, Chew, SPeak, Saez-Rodriguez, J, O'Neill, JS, Szabadkai, G, Minczuk, MA, Frezza, C
JournalMol Cell
Volume69
Issue4
Pagination581-593.e7
Date Published2018 Feb 15
ISSN1097-4164
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.

DOI10.1016/j.molcel.2018.01.034
Alternate JournalMol. Cell
Citation Key10.1016/j.molcel.2018.01.034
PubMed ID29452638
PubMed Central IDPMC5823973
Grant List / / Wellcome Trust / United Kingdom