Constitutive HIF-1α expression in the epidermis fuels proliferation and is essential for effective barrier formation.

Epidermis is one of the most rapidly proliferating tissues in the body with high demands for ATP and cellular building blocks. Here we show that, in order to meet these requirements, keratinocytes constitutively express hypoxia-inducible factor-1α (HIF-1α), even in the presence of oxygen levels sufficient for HIF-1α hydroxylation. We previously reported that mice with severe epidermal mitochondrial dysfunction actually showed a hyperproliferative epidermis, but rapidly died of systemic lactic acidosis and hypoglycemia, indicating excessive glycolysis. In the present work, we interrogated HIF-1α function in glycolysis by its epidermal ablation combined with mitochondrial dysfunction, which resulted in decreased proliferation but even earlier lethality due to a severe barrier defect. Our data demonstrate that HIF-1α is indispensable for maintaining a high aerobic glycolytic flux necessary for supplying energy, but also for synthetizing cellular building blocks like lipids, which are both essential for proliferation as well as barrier formation. HIF-1α is stabilized in keratinocytes in the presence of oxygen by high levels of HIF-1α transcripts, low levels of prolyl-4-hydroxylases (PHD2 and 3) and a low cellular α-ketoglutarate/lactate ratio, likely inhibiting PHD activity. Our data suggest a key role for constitutive HIF-1α expression allowing a Warburg-like metabolism in healthy, highly proliferative keratinocytes, similar to tumour cells.