TY  - JOUR
AU  - Boix, Julia
AU  - Knuever, Jana
AU  - Niehoff, Nadine
AU  - Sen, Ayesha
AU  - Pla-Martin, David
AU  - Baris, Olivier R
AU  - Etich, Julia
AU  - Brachvogel, Bent
AU  - Kaul, Harshita
AU  - Isbrandt, Dirk
AU  - Soroka, Ekaterina
AU  - Bazzi, Hisham
AU  - Wenger, Roland H
AU  - Giavalisco, Patrick
AU  - Wiesner, Rudolf J
TI  - Constitutive HIF-1α Expression in the Epidermis Fuels Proliferation and Is Essential for Effective Barrier Formation.
JO  - The journal of investigative dermatology
VL  - 145
IS  - 7
SN  - 0022-202X
CY  - Amsterdam
PB  - Elsevier
M1  - DZNE-2025-00753
SP  - 1683 - 1692.e8
PY  - 2025
AB  - Epidermis is one of the most rapidly proliferating tissues in the body with high demands for adenosine triphosphate and cellular building blocks. In this study, we show that to meet these requirements, keratinocytes constitutively express 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 this 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 such as 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 PHD3), and a low cellular a-ketoglutarate/lactate ratio, likely inhibiting prolyl-4-hydroxylase activity. Our data suggest a key role for constitutive HIF-1α expression allowing a Warburg-like metabolism in healthy, highly proliferative keratinocytes, similar to that in tumor cells.
KW  - Hypoxia-Inducible Factor 1, alpha Subunit: metabolism
KW  - Hypoxia-Inducible Factor 1, alpha Subunit: genetics
KW  - Animals
KW  - Cell Proliferation
KW  - Mice
KW  - Epidermis: metabolism
KW  - Epidermis: pathology
KW  - Keratinocytes: metabolism
KW  - Keratinocytes: cytology
KW  - Glycolysis
KW  - Mitochondria: metabolism
KW  - Epidermal barrier function (Other)
KW  - HIF-1α (Other)
KW  - Lipid synthesis (Other)
KW  - Mitochondrial DNA (Other)
KW  - Skin homeostasis (Other)
KW  - Hypoxia-Inducible Factor 1, alpha Subunit (NLM Chemicals)
KW  - Hif1a protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39580109
DO  - DOI:10.1016/j.jid.2024.09.022
UR  - https://pub.dzne.de/record/279376
ER  -