Fig. 2: ME1 induction promotes reductive carboxylation of glutamine.
From: Defective NADPH production in mitochondrial disease complex I causes inflammation and cell death
a Model illustrating the fate of fully labeled 13C glutamine after entering the TCA cycle. Glutamine oxidation generates M + 4 labeled substrates while its reductive carboxylation generates M + 3 labeled substrates. Note that ME1 activity is coupled to NADPH production and reduction of oxidized glutathione. b Percentage of labeled and unlabeled malate in ND1 mutant cells after 3 h incubation with 13C-labeled ([U-13C5]) glutamine (n = 3). c Isotopomer distribution of malate in sgNeg and sgME1 ND1 mutant cells cultured in the presence of 13C glutamine for 3 h (n = 3). d ME1 overexpression decreases malate M + 4 originated by oxidation of glutamine in the TCA cycle and increases malate M + 3 coming from reductive carboxylation of glutamine (n = 3). e 14C glutamine oxidation is reduced in ND1 mutant cells overexpressing ME1 (n = 3). f Supplementation of cell permeable dimethyl-malate (DM-malate), at the indicated doses, did not increase survival of ND1 under galactose conditions (n = 3). Experiments are represented as means ± SEM., n > 3 biological replicates. Asterisks denote *p < 0.05, **p < 0.01, or ***p < 0.001. Paired two-tailed Student’s t test in d, e and one-way ANOVA in f. Red dashed lines indicate initial seeding density.
