The Factor Inhibiting HIF Asparaginyl Hydroxylase Regulates Oxidative Metabolism and Accelerates Metabolic Adaptation to Hypoxia

Abstract

SummaryAnimals require an immediate response to oxygen availability to allow rapid shifts between oxidative and glycolytic metabolism. These metabolic shifts are highly regulated by the HIF transcription factor. The factor inhibiting HIF (FIH) is an asparaginyl hydroxylase that controls HIF transcriptional activity in an oxygen-dependent manner. We show here that FIH loss increases oxidative metabolism, while also increasing glycolytic capacity, and that this gives rise to an increase in oxygen consumption. We further show that the loss of FIH acts to accelerate the cellular metabolic response to hypoxia. Skeletal muscle expresses 50-fold higher levels of FIH than other tissues: we analyzed skeletal muscle FIH mutants and found a decreased metabolic efficiency, correlated with an increased oxidative rate and an increased rate of hypoxic response. We find that FIH, through its regulation of oxidation, acts in concert with the PHD/vHL pathway to accelerate HIF-mediated metabolic responses to hypoxia.

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

“…Interestingly, among the accumulated substrates, succinate and fumarate could also contribute to HIF stability [ 165 ]. The recent study confirms this opinion that the FIH in concert with PHD/VHL in rapidly response to hypoxia, in turn, altered metabolites lead to HIF stability [ 56 ]. And authentic study speculated that lipopolysaccharide produced by gram-negative bacteria potently enhance the TCA-cycle intermediate metabolites succinate, performing a role of stabilizing HIF-1α accompanied with increased interleukin-1β, which finally mediating inflammation [ 161 ].…”

“…In addition, under normoxia, an asparagine residue in the C-terminal activation domain of HIF-1α and HIF-2α is hydroxylated by factor inhibiting HIF (FIH), resulting in the inability of the region to bind to p300, thus weakening the activation of the HIF pathway. However, in hypoxia, due to the inactivation of FIH, HIF-1α and HIF-2α avoid being hydroxylated, and subsequently translocate into the nucleus to bind with ARNT and p300, leading to the activation of HIF target genes [ 56 ]. The effect of FIH on the HIF-α further deepens our understanding of the mechanisms governing the stability of HIF-α.…”

“…Under hypoxic conditions, G9a and GLP proteins were not hydroxylated, thus maintaining stability, resulting in H3K9 methylation with inhibitory effect on genes, and finally realizing the epigenetic regulation of FIH-G9a/GLP signaling axis on the invasion and metastasis of ovarian cancer [ 99 ]. FIH also has similar regulatory effects on HIF-1α and HIF-2α in physiological and pathological conditions [ 56 ]. Whether this indicates that G9a/GLP has direct effects on HIF-α activities via epigenetic regulation are still unknown.…”

O-cyclic phytosphingosine-1-phosphate stimulates HIF1α-dependent glycolytic reprogramming to enhance the therapeutic potential of mesenchymal stem cells

“…Hypoxia-inducible factor 1 (HIF1) is a major transcription factor that induces metabolic reprogramming via upregulation of anaerobic glycolysis and downregulation of oxidative phosphorylation 20,30 . HIF1 is activated through strict control of its alpha subunit (HIF1α) by transcription, translation, posttranslational modification like prolyl-or asparaginyl hydroxylation and ubiquitination, and microtubule-associated nuclear transportation.…”

“…Therefore, it has been suggested that HIF1α plays an important role in the HIF1-regulated metabolism. In fact, stabilizing HIF1α through loss of the factor inhibiting HIF (FIH) or through the oxidative dimerization of the prolyl hydroxylase domain protein 2 (PHD2) facilitates metabolic adaptation to hypoxia 30,35 . Previous studies showed that HIF1αoverexpressed MSC exhibits high immunomodulatory effects and high resistance to hypoxia-induced apoptosis 36,37 .…”