The impact of oxidative stress on eukaryotic iron metabolism.

The processes of iron uptake and distribution are highly regulated in mammalian cells. Expression of the transferrin receptor is increased when cells are iron-depleted, while expression of the iron sequestration protein ferritin is increased in cells that are iron-replete. Regulation of expression of proteins of iron uptake (transferrin receptor) and iron sequestration (ferritin) presumably ensures that levels of reactive free iron are not high in cells. Formation of reactive oxygen species occurs when free iron reacts with oxygen, and tight regulation of iron metabolism may enable cells to avoid engaging in destructive chemical reactions. Levels of intracellular iron are directly sensed by two iron sensing proteins. Iron regulatory protein 1 (IRP1) is a bifunctional protein; in cells that are iron-replete, IRP1 contains an iron-sulfur cluster and functions as cytosolic aconitase. In cells that are iron-depleted, IRP1 binds stem-loop structures in RNA transcripts known as iron responsive elements (IREs). Iron regulatory protein 2 (IRP2) binds similar stem-loop structures, but the mode of regulation of IRP2 is different in that IRP2 is rapidly degraded in iron-replete cells. The post-transcriptional regulation of genes of iron metabolism in mammalian cells ensures that cells have an adequate supply of iron, and also ensures that cells do not generate excess reactive oxygen species through the interaction of free iron and oxygen.