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. 2020 Jan 3;11:102. doi: 10.1038/s41467-019-13668-3

Fig. 5. TCA cycle metabolites regulate HIF-α stabilization.

Fig. 5

Under normoxia, HIF-α is hydroxylated by prolyl-hydroxylases (PHDs) and targeted for proteasomal degradation by von Hippel-Lindau (pVHL) complex. Under hypoxic conditions, PHDs activity is inhibited preventing HIF-α hydroxylation, which causes its stabilization. HIF-α then translocates to the nucleus where it associates with HIF-1β to activate transcription of HIF target genes involved in metabolism, angiogenesis, erythropoiesis, immune responses, and tumor invasion. In normoxia, ROS released from mitochondria and accumulated levels of the metabolites succinate, fumarate and L-2-HG can inhibit the activity of PHDs causing a pseudohypoxia state.