Journal Article

DZNE-2025-00753

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Constitutive HIF-1α Expression in the Epidermis Fuels Proliferation and Is Essential for Effective Barrier Formation.

Boix, J. ; Knuever, J. ; Niehoff, N. ; Sen, A. ; Pla-Martin, D. ; Baris, O. R. ; Etich, J. ; Brachvogel, B. ; Kaul, H. ; Isbrandt, D.DZNE* ; Soroka, E. ; Bazzi, H. ; Wenger, R. H. ; Giavalisco, P. ; Wiesner, R. J.

2025
Elsevier Amsterdam

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Please use a persistent id in citations: doi:10.1016/j.jid.2024.09.022

Abstract: 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.

Keyword(s): Hypoxia-Inducible Factor 1, alpha Subunit: metabolism (MeSH) ; Hypoxia-Inducible Factor 1, alpha Subunit: genetics (MeSH) ; Animals (MeSH) ; Cell Proliferation (MeSH) ; Mice (MeSH) ; Epidermis: metabolism (MeSH) ; Epidermis: pathology (MeSH) ; Keratinocytes: metabolism (MeSH) ; Keratinocytes: cytology (MeSH) ; Glycolysis (MeSH) ; Mitochondria: metabolism (MeSH) ; Epidermal barrier function ; HIF-1α ; Lipid synthesis ; Mitochondrial DNA ; Skin homeostasis ; Hypoxia-Inducible Factor 1, alpha Subunit ; Hif1a protein, mouse

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Contributing Institute(s):

1. Experimental Neurophysiology (AG Isbrandt)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2025

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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