Fig. 2

Scheme of the molecular actors driving α-KG reductive carboxylation in mitochondria upon hypoxia (a) and in cancer cells with ETC defects (b). Reductive carboxylation requires the elevation of the α-KG/citrate ratio and reduces α-KG to isocitrate that is subsequently converted to citrate. This latter is shuttled to the cytosol where it is used for the biosynthesis of lipids. Noteworthy, in both cases (a-b), ROS production by ETC and α-KGDC may induce the inhibition of aconitase and α-KGDC, thereby preventing citrate and α-KG oxidation, respectively. a Upon hypoxia (5–0.5% O₂ tension), HIF1 can participate to the increase of the α-KG/citrate ratio, by preventing both PDH and α-KGDC activity, in turn limiting citrate production and α-KG oxidation, respectively. (b) In cancer cells with ETC defects, the accumulation of NADH may lead to the inhibition of mitochondrial NADH-dehydrogenases (PDH, IDH, and α-KGDC), thus decreasing citrate production/oxidation and α-KG oxidation. Further, NADH increase may also promote NADPH-dependent IDH1/2 activity. Finally, it is important to note that NADH accumulation might also foster reductive carboxylation under low oxygen tension. The TCA metabolic flux is represented by blue arrows (), and () indicate the specific enzyme for each TCA cycle step. Ac-CoA (Acetyl-Coenzyme A; Aco (aconitase); Cit (citrate); Isocit (Isocitrate); Gln (Glutamine); α-KG (α-ketoglutarate)