Hypoxia induces a glycolytic complex in intestinal epithelial cells independent of HIF-1-driven glycolytic gene expression

Abstract

The metabolic adaptation of eukaryotic cells to hypoxia involves increasing dependence upon glycolytic adenosine triphosphate (ATP) production, an event with consequences for cellular bioenergetics and cell fate. This response is regulated at the transcriptional level by the hypoxia-inducible factor-1(HIF-1)-dependent transcriptional upregulation of glycolytic enzymes (GEs) and glucose transporters. However, this transcriptional upregulation alone is unlikely to account fully for the levels of glycolytic ATP produced during hypoxia. Here, we investigated additional mechanisms regulating glycolysis in hypoxia. We observed that intestinal epithelial cells treated with inhibitors of transcription or translation and human platelets (which lack nuclei and the capacity for canonical transcriptional activity) maintained the capacity for hypoxia-induced glycolysis, a finding which suggests the involvement of a nontranscriptional component to the hypoxia-induced metabolic switch to a highly glycolytic phenotype. In our investigations into potential nontranscriptional mechanisms for glycolytic induction, we identified a hypoxia-sensitive formation of complexes comprising GEs and glucose transporters in intestinal epithelial cells. Surprisingly, the formation of such glycolytic complexes occurs independent of HIF-1-driven transcription. Finally, we provide evidence for the presence of HIF-1α in cytosolic fractions of hypoxic cells which physically interacts with the glucose transporter GLUT1 and the GEs in a hypoxia-sensitive manner. In conclusion, we provide insights into the nontranscriptional regulation of hypoxia-induced glycolysis in intestinal epithelial cells.

The glucocorticoid dexamethasone inhibits HIF-1α stabilization and metabolic reprogramming in lipopolysaccharide-stimulated primary macrophages

“…3H ), both of these responses being Dex-sensitive. The almost immediate glycolytic response to LPS cannot depend on HIF-1α-mediated transcriptional changes; we speculate that it involves rapid assembly of pre-existing glycolytic enzymes into cytosolic complexes, as recently described in intestinal epithelial cells [ 46 ]. The shift to aerobic glycolysis after prolonged exposure to LPS was impaired by KC7F2 ( Fig.…”

Lactylation stabilizes DCBLD1 activating the pentose phosphate pathway to promote cervical cancer progression

“…HIF-1α is a key transcription factor promoting Warburg-like metabolism. HIF-1α regulates the expression of various enzymes within metabolic pathways [ 34 ], including pyruvate kinase M [ 35 ] and lactate dehydrogenase A [ 30 ]. In our study, HIF-1α was enriched in the DCBLD1 promoter, consequently increasing DCBLD1 expression.…”

Cigarette smoke causes a bioenergetic crisis in RPE cells involving the downregulation of HIF-1α under normoxia

“…We were able to restore glycolytic capacity by either incubating the cells under hypoxic conditions or treatment with Roxadustat, providing a direct link between CSE-dependent metabolic dysregulation and HIF-1α degradation under normoxia. Future research should also address whether CSE-induced downregulation of glycolytic flux is caused by disruption of the transcriptional activity of HIF-1 or by a recently reported mechanism by which HIF-1α is involved in the cytoplasmic formation of a metabolic complex involving several glycolytic enzymes [ 63 ].…”