Fig. 4

Mitochondrial signals that shape the HIF1-mediated metabolic and hypoxic adaptation in cancer cells. The hypoxic response may originate both from HIF1α stabilization, via the decrease in oxygen levels and the increase in the (L)-2-HG/α-KG ratio that lower PHDs activity, and from HIF1 activation, due to high ROS levels. In the first instance, reduced oxygen levels may inhibit the L2HGDH activity thereby decreasing (L)-2-HG conversion into α-KG, together with fostering ROS production. Additionally, the elevation of NADH levels in the mitochondria that stems from decreased respiration inhibits the malate-aspartate shuttle (MAS) and therefore mitochondrial NADH production from cytosolic reductive power. Both mitochondrial and cytosolic NADH accumulation foster the activity of the NADH-dependent enzymes MDH1/2, PHGDH and LDHA that convert α-KG into (L)-2-HG. Furthermore, the potential production of ROS by the ETC and α-KGDC might further promote HIF1 activation. Finally, both NADH and HIF1 may inhibit α-KGDC and PDH, further promoting α-KG accumulation, in turn converted into (L)-2-HG or utilized for lipid biosynthesis