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Abstract
ABSTRACTHypoxia inducible factors (HIFs) play vital roles in cellular maintenance of oxygen homeostasis. These transcription factors are responsible for the expression of genes involved in angiogenesis, metabolism, and cell proliferation. Here, we generate a detailed mathematical model for the enzyme kinetics of α-ketoglutarate-dependent HIF prolyl 4-hydroxylase domain (PHD) dioxygenases to simulate our in vitro data showing synergistic PHD inhibition by succinate and hypoxia in experimental models of succinate dehydrogenase loss, which phenocopy familial paraganglioma. Our mathematical model confirms the inhibitory synergy of succinate and hypoxia under physiologically-relevant conditions. In agreement with our experimental data, the model predicts that HIF1α is not stabilized under atmospheric oxygen concentrations, as observed. Further, the model confirms that addition of α-ketoglutarate can reverse PHD inhibition by succinate and hypoxia in SDH-deficient cells.
Highlights
Maintaining oxygen homeostasis is vital to many cellular processes
We show that this model predicts that succinate and hypoxia synergistically inhibit prolyl 4-hydroxylase domain (PHD), and this inhibition can be overcome by the addition of αKG
Model assumptions and limitations The challenges in modeling the Hypoxia inducible factors (HIFs) pathway are as follows: there are three PHD isoforms and each may differentially contribute to HIF regulation
Summary
Maintaining oxygen homeostasis is vital to many cellular processes. When a cell is deprived of oxygen, ATP production drastically decreases from 36 to 2 ATP molecules per molecule of glucose metabolized. To sense and adapt to a low oxygen environment, mammalian cells rely on two key mediators, HIF1α and HIF2α (hypoxic-inducible factors; referred to as HIFα) (Pugh and Ratcliffe, 2003; Wenger, 2002). HIFs are transcription factors with an oxygen sensitive alpha-subunit (HIFα) and a constitutively expressed beta-subunit (HIFβ). The enzymatic rate of PHD decreases allowing HIFα to remain stable and translocate to the nucleus, where it can dimerize with HIFβ to form transcriptionally active HIF complex. The HIF complex activates genes involved in glucose uptake, energy metabolism, angiogenesis, erythropoiesis, cell proliferation and apoptosis (Pugh and Ratcliffe, 2003; Wenger, 2002)
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