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Science 17 December 2004:
Vol. 306. no. 5704, pp. 2087 - 2090
DOI: 10.1126/science.1103786
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Reports

Mammalian Tissue Oxygen Levels Modulate Iron-Regulatory Protein Activities in Vivo

Esther G. Meyron-Holtz, Manik C. Ghosh, Tracey A. Rouault*

The iron-regulatory proteins (IRPs) posttranscriptionally regulate expression of transferrin receptor, ferritin, and other iron metabolism proteins. Although both IRPs can regulate expression of the same target genes, IRP2–/– mice significantly misregulate iron metabolism and develop neurodegeneration, whereas IRP1–/– mice are spared. We found that IRP2–/– cells misregulated iron metabolism when cultured in 3 to 6% oxygen, which is comparable to physiological tissue concentrations, but not in 21% oxygen, a concentration that activated IRP1 and allowed it to substitute for IRP2. Thus, IRP2 dominates regulation of mammalian iron homeostasis because it alone registers iron concentrations and modulates its RNA-binding activity at physiological oxygen tensions.

Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.

* To whom correspondence should be addressed. E-mail: trou{at}helix.nih.gov

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