Title: Deficiency or inhibition of oxygen sensor PHD1 induces hypoxia tolerance by reprogramming basal metabolism
Authors: Aragonés, Julián *
Schneider, Martin *
Van Geyte, Katie
Fraisl, Peter
Dresselaers, Tom
Mazzone, Max
Dirkx, Ruud
Zacchigna, Serena
Lemieux, Hélène
Jeoung, Nam Ho
Lambrechts, Diether
Bishop, Tammie
Lafuste, Peggy
Diez-Juan, Antonio
Harten, Sarah K
Van Noten, Pieter
De Bock, Katrien
Willam, Carsten
Tjwa, Marc
Grosfeld, Alexandra
Navet, Rachel
Moons, Lieve
Vandendriessche, Thierry
Deroose, Christophe
Wijeyekoon, Bhathiya
Nuyts, Johan
Jordan, Benedicte
Silasi-Mansat, Robert
Lupu, Florea
Dewerchin, Mieke
Pugh, Chris
Salmon, Phil
Mortelmans, Luc
Gallez, Bernard
Gorus, Frans
Buyse, Johan
Sluse, Francis
Harris, Robert A
Gnaiger, Erich
Hespel, Peter
Van Hecke, Paul
Schuit, Frans
Van Veldhoven, Paul P
Ratcliffe, Peter
Baes, Myriam
Maxwell, Patrick
Carmeliet, Peter # ×
Issue Date: Feb-2008
Publisher: Nature America, Inc.
Series Title: Nature Genetics vol:40 issue:2 pages:170-180
Abstract: HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparalpha pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress.
ISSN: 1061-4036
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Animal Physiology and Neurobiology Section - miscellaneous
Vesalius Research Centre (-)
Biomedical MRI
Molecular and Cellular Medicine - miscellaneous (-)
Exercise Physiology Research Group
Department of Movement Sciences - miscellaneous
Molecular and Vascular Biology
Clinical Residents Medicine
Nuclear Medicine & Molecular Imaging
Division of Livestock-Nutrition-Quality (-)
Biochemistry Section (Medicine) (-)
Pharmacology Section (-)
Cell Metabolism
Gene Expression Unit
Laboratory of Lipid Biochemistry and Protein Interactions
Laboratory of Translational Genetics (VIB-KU Leuven Center for Cancer Biology)
Laboratory of Tumor Inflammation and Angiogenesis (VIB-KU Leuven Centre for Cancer Biology) (+)
Laboratory of Angiogenesis and Vascular Metabolism (VIB-KU Leuven Centre for Cancer Biology) (+)
* (joint) first author
× corresponding author
# (joint) last author

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