Give Me Oxygen (or Not)

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Science  25 Jan 2008:
Vol. 319, Issue 5862, pp. 387
DOI: 10.1126/science.319.5862.387d

Recent memorial tributes celebrating the accomplishments of Sir Edmund Hillary, one of the first two men to scale Mount Everest, are a fascinating reminder of the ability of mammals to tolerate low oxygen levels (hypoxia). The physiological response to hypoxia involves the transmission of signals from cellular oxygen-sensing pathways to metabolic enzymes that consume oxygen, but how this occurs is poorly understood. Aragonés et al. have studied mice that are deficient in an oxygen-sensitive enzyme that regulates the stability of a transcription factor (hypoxia-inducible factor-1), which is known to activate genes involved in cellular adaptations to hypoxia. Analysis of skeletal muscle in the mutant mice revealed that the loss of this enzyme, called prolyl hydroxylase-1 (Phd1), lowered oxygen consumption by reprogramming basal metabolism; that is, by inducing a selective decrease in glucose oxidation and a switch to more anaerobic glycolysis. Muscle tissue in the Phd1-deficient mice was protected from the necrosis typically seen under acute oxygen deprivation, an outcome apparently due to reduced formation of harmful reactive oxygen species. These findings not only identify Phd1 as a key molecular player regulating hypoxia tolerance but raise the possibility that pharmacological inhibition of the enzyme could have beneficial effects in diseases characterized by oxidative stress and ischemic damage. — PAK

Nat. Genet. 40, 10.1038/ng.2007.62 (2008).

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