Figure 3.
Metabolic shifts in hypoxia: the role of Hif1 and miR-210 in reductive stress. The Hif1 nuclear factor mediates the metabolic response to hypoxia. Hif1 upregulates genes involved in glucose uptake and glycolysis and decreases the entry of pyruvate into the citric acid cycle by the upregulation of pyruvate dehydrogenase kinase, a suppressor of pyruvate dehydrogenase. The Hif-mediated upregulation of miR-210 reinforces the decrease carbon flux through the TCA cycle and the reduction of oxidative phosphorylation under limited oxygen. miR-210 decreases the expression of the iron sulfur-cluster assembly enzyme (ISCU1/2) to suppress the synthesis of iron-sulfur clusters (FeS), decreasing the activity of enzymes such as aconitase, a TCA cycle enzyme. FeS clusters are also important for electron transfer in subunits of complex I, complex II, and complex III. Furthermore, miR-210 directly targets genes involved in the electron transport chain (ETC) complexes, such as NDUFA4, a complex I component; SDHD, a complex II subunit; and COX10, a complex IV component. Decreased complex I activity leads to accumulation of NADH. In addition, multiple pathways augment the electron flux from NADH to NADPH. Under hypoxia, compensatory pathways (such as glutamine utilization) lead to an increase in 2-oxoglutarate and its subsequent reduction to L(S)-2-hydroxyglutarate (L2HG) by malate dehydrogenase and other enzymes. Experimental evidence suggests that L2HG inhibits glycolysis and that the pentose phosphate pathway (PPP) is upregulated in hypoxia.