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

[en] 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.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Aragones, Julian

Schneider, Martin

Van Geyte, Katie

Fraisl, Peter

Dresselaers, Tom

Mazzone, Massimiliano

Dirkx, Ruud

Zacchina, Serena

Lemieux, Hélène

Jeoung, Nam Ho

More authors (37 more)

Language :

English

Title :

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

Publication date :

2008

Journal title :

Nature Genetics

ISSN :

1061-4036

eISSN :

1546-1718

Publisher :

Nature Publishing Group, New York, United States - New York

Volume :

Pages :

170-180

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 18 December 2009

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404

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313

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