Albertine Donker

General Introduction 19 1 ◀ Abbreviations: ACVR2A denotes Activin receptor type 2A; ALK, Activin receptor-like kinase; BMP, bone morphogenetic protein; BMPR2, BMP receptor 2; BMP-RE, BMP-responsive element; ERFE, erythroferrone; GDF15, growth differentiation factor 15; HJV, hemojuvelin; IL6, interleukin 6; IL6R, IL6 receptor; LSEC, liver sinusoidal endothelial cell; MT2, matriptase 2; R-SMAD, receptor-activated SMAD; sHJV, soluble HJV; SMAD, Sons of mothers against decapentaplegic; STAT3, signal transducer and activator of transcription 3; STAT-RE, STAT-responsive element; TBI, transferrin-bound iron; TfR2, transferrin receptor 2; TWSG1, twisted gastrulation 1. Figure adapted from Muckenthaler et al , 2017. 11 Human cells acquire iron predominantly via TfR1-mediated endocytosis of TBI. In the endosomes, iron is freed from Tf and reduced from Fe 3+ to Fe 2+ by a metalloreductase, such as Six-transmembrane epithelial antigen of prostate 3 (STEAP3), prior to its release into the cytosol via Divalent Metal Transporter 1 (DMT1). Of note, DMT is also responsible for the apical resorption of dietary iron after reduction by the ferrireductase duodenal cytochrome B (DCYTB). Apotransferrin and TfR1 return to the plasma membrane to be re-used for next cycles. 15 Biochemical and genetic studies suggests that also transferrin-independent routes of iron uptake exist. Both zinc-regulated transporter (ZRT)/iron-regulated transporter (IRT)-like protein ZIP14 and DMT1 seem to be implicated in non-transferrin-bound iron (NTBI) uptake. 42-45 Duodenal enterocytes are also able to acquire iron in the form of heme iron. Ingested heme comprises one third of dietary iron but up to two-thirds of absorbed body iron due to the increased bioavailability of heme iron relative to non-heme iron. Although the molecule(s) mediating duodenal enterocyte heme uptake at the brush border has/have not been identified, considerable evidence suggests that uptake occurs via a receptor-mediated endocytosis pathway or by a heme importer, possibly heme carrier protein 1(HCP1). 46 After the iron has arrived inside the cell, it is stored in the so-called labile iron pool (LIP). The LIP is utilized for direct incorporation into iron proteins or iron transport into mitochondria via mitoferrin (MFRN), where the metal is inserted into heme or Fe/S cluster prosthetic groups. The fraction of the LIP that is not utilized for heme or Fe/S cluster synthesis, can be stored inside the cell as ferritin or exported out of the cell via FPN in the form of Fe 2+ , after which it is oxidized to Fe 3+ in order to bind to Tf.