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Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism

Nature Genetics volume 40, pages 170–180 (2008)Cite this article

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 Pparα 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-2α 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.

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Figure 1: Loss of Phd1 reduces oxygen consumption.
Figure 2: Loss of Phd1 reprograms muscle glucose metabolism.
Figure 3: Hypoxia tolerance in ischemic Phd1-deficient muscle.
Figure 4: Reduced oxidative stress and energy production in ischemic Phd1-deficient muscle.
Figure 5: Role of Pparα and Hif-2α, and hypoxia tolerance by knockdown of Phd1.
Figure 6: Loss of Phd1 induces hypoxia tolerance.

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Acknowledgements

J.A. is sponsored by the Centro Nacional de Investigaciones Cardiovasculares (CNIC; Spain) and Flanders Institute of Biotechnology (VIB; Belgium); M.S. by the Deutsche Forschungsgemeinschaft (Germany) and the Lymphatic Research Foundation; K.V.G. by a doctoral fellowship from the K.U. Leuven; P.F. by a postdoctoral fellowship from the K.U. Leuven; and H.L. by a postdoctoral fellowship from Fond Québécois de la nature et des technologies. This work is supported, in part, by grant GOA2006/11/KULeuven from the University of Leuven, Belgium, grant IUAP05/02 from the Federal Government Belgium, grants FWO G.0265 and FWO G.0387 from the Flanders Research Foundation, Belgium, grant 5RO1GM037704 from the US National Institutes of Health (to F.L.), grant 12RO1DK47844 from the US National Institutes of Health (to R.A.H.), grant 2.4532.03 from the Belgian Fonds National de la Recherche Scientifique (to F.S.), and a grant from the Molecular Small Animal Imaging Center, University of Leuven (to L.M. and P.V.H.) and by a Programme Grant from the British Heart Foundation (to P.H.M. and P.J.R.). The authors thank A. Bouche, A. Carton, P. Chevron, M. De Mol, E. Gils, B. Hermans, L. Kieckens, W.Y. Man, W. Martens, A. Manderveld, E. Meyhi, L. Notebaert, J. Souffreau, C. Vanhuylebroeck, B. Vanwetswinkel, P. Van Wesemael, Q. Swennen, B. Kamers and S. Wyns for their contributions.

Author information

Author notes

  1. Martin Schneider & Carsten Willam

    Present address: Current addresses: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany (M.S.) and Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany (C.W.).,

  2. Julián Aragonés, Martin Schneider, Katie Van Geyte and Peter Fraisl: These authors contributed equally to this work.

Authors and Affiliations

  1. The Center for Transgene Technology and Gene Therapy, Katholieke Universiteit (K.U.) Leuven, Leuven, B-3000, Belgium

    Julián Aragonés, Martin Schneider, Katie Van Geyte, Peter Fraisl, Massimiliano Mazzone, Serena Zacchigna, Diether Lambrechts, Peggy Lafuste, Antonio Diez-Juan, Marc Tjwa, Lieve Moons, Thierry Vandendriessche, Mieke Dewerchin & Peter Carmeliet

  2. Department of Transgene Technology and Gene Therapy, Flanders Institute for Biotechnology (VIB), Leuven, B-3000, Belgium

    Julián Aragonés, Martin Schneider, Katie Van Geyte, Peter Fraisl, Massimiliano Mazzone, Serena Zacchigna, Diether Lambrechts, Peggy Lafuste, Antonio Diez-Juan, Marc Tjwa, Lieve Moons, Thierry Vandendriessche, Mieke Dewerchin & Peter Carmeliet

  3. Biomedical MRI Unit, K.U. Leuven, Leuven, B-3000, Belgium

    Tom Dresselaers & Paul Van Hecke

  4. Laboratory of Cell Metabolism, K.U. Leuven, Leuven, B-3000, Belgium

    Ruud Dirkx & Myriam Baes

  5. Department of Transplant Surgery, Medical University of Innsbruck, D. Swarovski Research Laboratory, Innsbruck, A-6020, Austria

    Hélène Lemieux & Erich Gnaiger

  6. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, 46202, Indiana, USA

    Nam Ho Jeoung & Robert A Harris

  7. The Henry Wellcome Building for Molecular Physiology, Oxford, 7BN, OX3, UK

    Tammie Bishop, Carsten Willam, Alexandra Grosfeld, Bhathiya Wijeyekoon, Chris Pugh & Peter Ratcliffe

  8. Division of Medicine, Hammersmith Campus, Imperial College London, London, W12 ONN, UK

    Sarah K Harten & Patrick Maxwell

  9. Exercise and Health Laboratory, Faculty of Kinesiology and Rehabilitation Sciences, K.U. Leuven, Leuven, B-3001, Belgium

    Pieter Van Noten, Katrien De Bock & Peter Hespel

  10. Department of Life Sciences, Laboratory of Bioenergetics and Molecular Physiology, University of Liege, Liege, 4000, Belgium

    Rachel Navet & Francis Sluse

  11. Department of Nuclear Medicine, University Hospital, K.U. Leuven, Leuven, B-3000, Belgium

    Christophe Deroose, Johan Nuyts & Luc Mortelmans

  12. Biomedical Magnetic Resonance Unit, Medicinal Chemistry and Radiopharmacy, U.C. Louvain, Brussels, B-1200, Belgium

    Benedicte Jordan & Bernard Gallez

  13. Cardiovascular Research Program, Oklahoma Medical Research Foundation, Oklahoma, 73104, USA

    Robert Silasi-Mansat & Florea Lupu

  14. Skyscan NV, Aartselaar, B-2630, Belgium

    Phil Salmon

  15. Diabetes Research Center, Free University of Brussels, Brussels, B-1090, Belgium

    Frans Gorus

  16. Department of Biosystems, Laboratory for Physiology, Immunology and Genetics of Domestic Animals, K.U. Leuven, Leuven, B-3001, Belgium

    Johan Buyse

  17. Department of Molecular Cell Biology, Gene Expression Unit, K.U. Leuven, Leuven, B-3000, Belgium

    Frans Schuit

  18. Department of Molecular Cell Biology, Laboratorium for Lipid Biochemistry and Protein Interactions (LIPIT), K.U. Leuven, B-3000, Belgium

    Paul Van Veldhoven

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  1. Julián Aragonés
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Contributions

J.A.: analysis of all data; design and performance of NMR spectroscopy, assays of metabolic enzymes, metabolites, indirect calorimetry, RNA and protein expression, and respiration studies; writing of the paper. M.S.: analysis of all data; design and performance of running tests, hind limb vascularization, EPR, respiration studies, indirect calorimetry and histological analysis; writing of the paper. K.V.G.: analysis of all data; design and performance of RNA interference experiments, metabolic assays, indirect calorimetry and RNA and protein expression; writing of the paper. P.F.: analysis of all data; design and performance of metabolic assays and mitochondrial respiration studies; writing of the paper. T.D. and P.V.H.: NMR spectroscopy. M.M., P.L., S.K.H., A.G., S.Z. and T.B.: protein expression analysis, cell culture experiments, mitochondrial performance assays. N.H.J., F.G., R.A.H. and R.D.: metabolic enzyme and metabolite assays; oxidative stress assays. D.L. and M.D.: generation of PHD1-deficient mice; genetic analysis of background; statistical analysis. A.D.-J. and T.V.: design of constructs expressing interference short hairpin RNAs. P.V.N., K.D.B. and P.H.: muscle exercise studies. C.W. and C.P.: design and construction of PHD1 targeting vector. M.T. and L. Moons.: histological analysis. R.N. and F. Sluse.: mitochondrial respiration studies. C.D., B.W., J.N. and L. Mortelmans: glucose metabolism studies. B.J. and B.G.: EPR studies. R.S.-M. and F.L.: mitochondrial ultrastructure. P.S.: micro-CT analysis. J.B.: indirect calorimetry. H.L. and E.G.: analysis and performance of mitochondrial respiration studies in isolated myofibers. P.V.V., F. Schuit and M.B.: analysis and design of metabolic experiments and oxidative stress assays; writing of the paper. P.R., P.M and P.C.: scientific direction; generation of PHD knockout mice; conception of hypoxia tolerance studies; design of experimental approaches; analysis of data; writing of the paper.

Corresponding author

Correspondence to Peter Carmeliet.

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Competing interests

P.H.M. is a director, consultant and equity holder in ReOx Ltd. P.J.R., P.H.M and C.W.P. are founding scientists of ReOx Ltd.

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Aragonés, J., Schneider, M., Van Geyte, K. et al. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet 40, 170–180 (2008). https://doi.org/10.1038/ng.2007.62

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