Albertine Donker

General Introduction 13 1 PHYSIOLOGY OF SYSTEMIC AND CELLULAR IRON METABOLISM The vast majority of human body iron is dedicated to hemoglobin synthesis The human adult body produces 20 mL blood every day, consisting of 200 x 10 9 red blood cells (RBC’s). The cytoplasm of RBC’s is rich of hemoglobin, an iron-containing bio-molecule that plays a crucial role in oxygen transport. Twenty milligrams of iron every day and 2x 10 15 iron atoms every second are required for this enormous production, illustrating that the majority of body iron is involved in maintaining adequate erythropoiesis. 11 In the human body iron alternates between the oxidation states Fe 2+ (ferrous iron) and Fe 3+ (ferric iron). This interconversion between Fe 2+ and Fe 3+ involves a mechanism whereby iron not only participates in electron transfer, but also has the ability to reversibly bind ligands. These fundamental biochemical characteristics of iron are the basis for its essential roles in many biological processes, e.g. oxygen transport via the heme component of hemoglobin, cellular respiraton as part of heme-containing cytochromes and iron-sulfur (Fe/S) cluster- containing proteins of the electron transport chain, DNA synthesis and cell growth, cell differentiation and regulation of gene expression. 12 In young children, iron plays an important role in brain growth and development, making them vulnerable to ID. 3,12 On the other hand, iron is a potential toxicant to cells. Unbound iron can catalyze the formation of oxidative radicals that damage proteins, lipids and nucleic acids. Furthermore, many pathogens are dependent of iron for their survival. 13,14 Because both ID and IO may have detrimental effects, a highly sophisticated regulatory system is required to maintain iron homeostasis on both the systemic and cellular level. 11 Extensive research of the last 20 years revealed that iron metabolism is balanced by two regulatory systems, one that functions systemically and relies on the hormone hepcidin and the cellular iron exporter ferroportin (FPN), and another that predominantly controls cellular iron metabolism through iron-regulatory proteins (IRP’s) that bind iron-responsive elements (IRE’s) in regulated messenger RNA’s of cellular iron importers, exporters and storage genes. Although the machineries of systemic and cellular iron homeostasis are separated, crosstalk exists between the two distinct control systems 11,15,16