Figure 2.

Mechanisms of hypoxic adaptation. (a) In normoxia, hypoxia inducible factor-1α (HIF-1α) is degraded, following O₂-dependent hydroxylation by prolyl hydroxylase (PHD) enzymes. (b) In hypoxia, HIF-1α spontaneously accumulates and combines with HIF-1β in the nucleus to activate the transcription of hypoxia-responsive genes and driving a number of metabolic adaptations: (i) BNIP3 upregulation leads to mitochondrial autophagy; (ii) a subunit switch at cytochrome c oxidase (COX), complex IV of the electron transport chain, increases the efficiency of electron (e^-) transfer, and attenuates reactive oxygen species (ROS) production; (iii) glycolytic enzymes and lactate dehydrogenase (LDH) are upregulated, increasing anaerobic ATP production and lactate; (iv) pyruvate dehydrogenase kinase (PDK) enzymes are upregulated, de-activating pyruvate dehydrogenase (PDH) and limiting the conversion of pyruvate to acetyl CoA.