Albertine Donker

General Introduction 21 1 duodenal DMT1 and FPN, resulting in higher transfer of iron from the diet via the plasma to the erythroblasts at the expense of iron depletion of the enterocytes. 48,49 Conversely, in iron replete conditions the IRE/IRP system mediates HIF2α and FPN mRNA translation but also promotes the degradation of HIF2α and FPN via iron- and oxygen dependent signals and hepcidin respectively. 11,48,49 To summarize, the hepcidin/FPN and IRE/IRP system control the systemic and cellular iron homeostasis respectively via distinct regulatory pathways. However, as described above, connections exist between the two systems on the level of FPN, HIF2α and TfR1. 15,48 First, FPN, that is a critical factor in iron supply to the plasma since it is the only known cellular iron exporter, is subject to both systems. Iron status is sensed on the systemic level and communicated post-translationally via hepcidin, thereby influencing the activity of FPN. On the cellular level, iron levels post-transcriptionally regulate FPN mRNA via the IRE/IRP system. 49 Second, HIF2α is involved in EPO-mediated regulation of hepcidin levels but HIF2α mRNA is also a target of the IRE/IRP system. Third, systemic Tf-Fe 2 displaces TfR1 from HFE inside the hepatocyte, which then subsequently forms a complex with TfR2 and HJV to promote BMP/SMAD signaling leading to HAMP transcription, whereas TfR1 expression is modulated by the IRE/IRP system. 15,27 More interconnections between the systemic and cellular iron homeostasis might exist and although the cornerstones of the two systems have been identified, future research is needed to further unravel how the two systems tango and collaborate. Heme Biosynthesis consists of eight enzymatic reactions in both the mitochondria and cytosol and is regulated by the activity of ALAS2 The vast majority of ingested and recycled iron is dedicated to heme synthesis, which plays a crucial role in many fundamental processes because of its oxidation- reduction capacity. 11 Heme serves as the prosthetic group of numerous hemoproteins, a large group of proteins that includes cytochromes (for mitochondrial respiratory chain electron transfer and drug metabolism), oxidases (e.g., nicotinamide adenine dinucleotide phosphate (NADPH) oxidase) and peroxidases, catalases and synthases (e.g., nitric oxide synthase, NOS), as well as the oxygen storage and transport molecules, myoglobin and hemoglobin (Hb). 46,50 Furthermore, heme is essential for the regulation of microRNA processing, protein synthesis and cell differentiation, 51 circadian rhythm 52 and ion-channel functions. 53