Fig 3. Glutamine is a key metabolite for anaplerosis during de novo fatty acid synthesis and can be utilized via different pathways under different conditions.

(A) Reactions in the TCA cycle. The citrate removed from the TCA cycle for use as a substrate for fatty acid synthesis is replenished by the α-ketoglutarate generated from glutamine. (B) At high rates of de novo fatty acid synthesis (indicated by high ACC activity), our model predicts that the TCA cycle will shut down at low glutamine concentrations. Here, the flux through the enzyme α-ketoglutarate dehydrogenase is shown as the TCA cycle flux. (C) High glutamine availability can drive a large fatty acid synthesis flux. (D) Glutamine can be utilized for fatty acid synthesis via distinct pathways under normoxic and hypoxic conditions. (E) Under hypoxic conditions, glutamine can be utilized via the reductive carboxylation pathway (see panel D). High activity of NADPH-dependent IDH is essential for reductive carboxylation. (F) Ratio of the concentration of different TCA cycle intermediates under normoxic conditions to the concentration under hypoxic conditions. The panel also shows the ratio of the mitochondrial NAD⁺:NADH ratios under the two conditions. Since the NADPH-dependent IDH pathway (active under hypoxic conditions) skips the TCA cycle reactions, activation of this pathway is accompanied by a decrease in the mitochondrial concentrations of multiple TCA cycle intermediates. Fluxes are in units of mM h^-1 (millimolar per hour) and are shown at steady state.