Disentangling iron regulatory networks

Imbalances of iron homeostasis underlie some very frequent clinical conditions, including iron-deficient anemia and hereditary hemochromatosis, the latter being possibly the most common inherited disorder in people of northern European origin leading to progressive iron overload and subsequent organ damage. The orchestration of cellular iron homeostasis is, thus, a leading priority for organisms which can be referred to the crucial role of iron for oxygen transport, for cellular energy supply, for function as a cofactor of enzymes involved in oxidative phosphorylation, for DNA synthesis due to the metal's role in ribonucleotide reductase, for cellular differentiation by influencing the activity of cyclins, for immune function by modulating cytokine activities and lymphocyte proliferation, or for redox regulation in being a catalyst for radical formation.

With the increasing number of iron-susceptible target genes and the identification of divergent fine-tuners of iron homeostasis, the iron regulatory networks have become more difficult to survey.

In this issue, Muckenthaler and coworkers (page 3690) present a study employing a microarray technique to screen for iron inducible genes by means of a self-designed “iron chip.” The functionality and reliability of this method has been underscored by the authors upon investigation of the effect of various modulators of iron homeostasis such as iron salts, nitric oxide, or hydrogen peroxide on the expression of iron controlled genes. Studies such as this may open the door to a new area in iron research in which screening of an enormous number of target genes toward iron-mediated regulation can easily be performed. Subsequent functional investigations will then provide more insights into the regulatory networks of iron biology under physiologic and pathologic conditions. Finally, “iron chips” may turn out to be of practical value in clinics, for example, to screen for inherited or acquired defects of iron homeostasis and its metabolic consequences.