Figure 1. TCA cycle dysfunction in SDH-deficient cells.

Loss of succinate dehydrogenase leads to perturbations in amino-acid metabolism, TCA cycle dysfunction and aerobic glycolysis. (a) Abundance of alanine, aspartate and glutamate decrease in imCC Sdhb-null (KO c6 and c8) cells relative to wild-type (WT) control, as assessed using GC–MS (n=3). ****P<0.0001 as calculated by a Kruskal–Wallis test. (b) Steady-state succinate, aspartate and asparagine in SDH-mutated patients’ tumours (n=3) compared with non-SDH mutated tumours (n=3). As expected, succinate is significantly increased, whereas aspartate and asparagine are decreased. (c) Abundance of succinate, fumarate, malate and citrate are significantly altered in Sdhb-KO imCC (c6 and c8) cells relative to WT control, as assessed using GC–MS (n=3). ****P<0.0001 as calculated by a Kruskal–Wallis test. (d) SDH-deficient cells exhibit aerobic glycolysis as shown by increase lactate production from glucose. After 24 h of incubation with medium containing ¹³C-[1,2]-glucose, the media were extracted and the abundance of different mass isotopomers of lactate excreted were quantified using NMR spectroscopy. ¹³C atoms (arising from glucose) are shown as filled circles, whereas ¹²C atoms are empty circles (n=3). All error bars shown represent s.d.