1: Nat Genet. 2008 Feb;40(2):170-80. Epub 2008 Jan 6.

Comment in:
    Nat Genet. 2008 Feb;40(2):132-4.

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

Aragonés J, Schneider M, Van Geyte K, Fraisl P, Dresselaers T, Mazzone M, Dirkx
R, Zacchigna S, Lemieux H, Jeoung NH, Lambrechts D, Bishop T, Lafuste P,
Diez-Juan A, Harten SK, Van Noten P, De Bock K, Willam C, Tjwa M, Grosfeld A,
Navet R, Moons L, Vandendriessche T, Deroose C, Wijeyekoon B, Nuyts J, Jordan B, 
Silasi-Mansat R, Lupu F, Dewerchin M, Pugh C, Salmon P, Mortelmans L, Gallez B,
Gorus F, Buyse J, Sluse F, Harris RA, Gnaiger E, Hespel P, Van Hecke P, Schuit F,
Van Veldhoven P, Ratcliffe P, Baes M, Maxwell P, Carmeliet P.

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

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.


PMID: 18176562 [PubMed - indexed for MEDLINE]

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