The long history of iron in the Universe and in health and disease

Abstract

Background: Not long after the Big Bang, iron began to play a central role in the Universe and soon became mired in the tangle of biochemistry that is the prima essentia of life. Since life's addiction to iron transcends the oxygenation of the Earth's atmosphere, living things must be protected from the potentially dangerous mix of iron and oxygen. The human being possesses grams of this potentially toxic transition metal, which is shuttling through his oxygen-rich humor. Since long before the birth of modern medicine, the blood-vibrant red from a massive abundance of hemoglobin iron-has been a focus for health experts.

Scope of review: We describe the current understanding of iron metabolism, highlight the many important discoveries that accreted this knowledge, and describe the perils of dysfunctional iron handling.

General significance: Isaac Newton famously penned, "If I have seen further than others, it is by standing upon the shoulders of giants". We hope that this review will inspire future scientists to develop intellectual pursuits by understanding the research and ideas from many remarkable thinkers of the past.

Major conclusions: The history of iron research is a long, rich story with early beginnings, and is far from being finished. This article is part of a Special Issue entitled Transferrins: Molecular mechanisms of iron transport and disorders.

Figure 1. Mammalian iron cycle

(A) Scheme depicting quantitative aspects of normal iron kinetics based on measurements of an ⁵⁹Fe disappearance curve, ⁵⁹Fe incorporation into erythrocytes and its surface counting (reproduced from Pollycove and Mortimer [1], with permission). As discussed in section 1.2, it is unlikely that the “Erythropoietic labile pool” represents iron released from the interior of bone marrow erythroblasts. Rather, this pool probably represents iron derived from hemoglobin degraded in bone marrow macrophages as a result of normal ineffective erythropoiesis [408] and hemoglobin released during the enucleation of orthochromatic erythroblasts [409]. Ferrokinetic studies yield higher values for ineffective erythropoiesis (i.e., “erythropoietic labile pool”) than studies based on measurement of the incorporation of [¹⁵N]ALA into early labelled bilirubin; hence, it cannot be excluded that ferrokinetic studies (that include inaccurate radioactivity measurements over the body surface) produce inflated values. The Polycove-Mortimer scheme, published in 1961, is being reproduced or reprinted after minor modifications ever since: (B) shows one of the current versions [395].

Figure 2. Cellular iron metabolism

Most cells acquire iron by transferrin receptor (TfR)-mediated endocytosis of diferric transferrin (Tf) followed by the internalization of Tf-TfR complexes, eventuating in an acidified compartment whose pH promotes the release of iron from Tf. The iron is reduced by Steap3 and then released from Tf and then endosome through DMT1. The immediate fate of this released iron is unknown up to the point where it is transported across the inner mitochondrial membrane by Mfrn1 or Mfrn2. In mitochondria, iron is assembled into heme and iron sulfur clusters (Fe/S). Some of the heme is exported though an unknown mechanism for use by ER, peroxisomal, cytosolic, or nuclear hemoproteins. A not yet characterized intermediate (or possibly Fe/S cluster product) of the Fe/S biogenesis pathway (X) is exported through ABCB7 for the formation of extramitochondrial Fe/S cluster proteins. Iron outside of any subcellular compartment is comprised by the labile iron pool (“LIP”). Excess iron is stored in the ubiquitous iron storage protein, ferritin. Some cells may also export iron, also presumably from the LIP, by ferroportin (FPN).

Figure 3. Close-up of ligands and second shell residues in human serum transferrin

N-lobe ligands are on the left and colored green (PDB 1A8E). Second shell residues are depicted in yellow. The conserved arginine is in purple. C-lobe ligands from porcine Tf are shown on the right with the same color scheme and with human numbering (1H76). Figure produced with PyMOL by Ashely N. Steere.