Oxidative Stress and the Homeodynamics of Iron Metabolism

Abstract

Iron and oxygen share a delicate partnership since both are indispensable for survival, but if the partnership becomes inadequate, this may rapidly terminate life. Virtually all cell components are directly or indirectly affected by cellular iron metabolism, which represents a complex, redox-based machinery that is controlled by, and essential to, metabolic requirements. Under conditions of increased oxidative stress-i.e., enhanced formation of reactive oxygen species (ROS)-however, this machinery may turn into a potential threat, the continued requirement for iron promoting adverse reactions such as the iron/H2O2-based formation of hydroxyl radicals, which exacerbate the initial pro-oxidant condition. This review will discuss the multifaceted homeodynamics of cellular iron management under normal conditions as well as in the context of oxidative stress.Keywords: iron; oxidative stress; metabolism Systemic and Cellular Iron TransfersFerric iron or iron contained in heme is absorbed by intestinal enterocytes via heme carrier proteins (HCP1) [1], the divalent metal transporter DMT1 (SLC11A2) [2,3] or the integrin-mobilferrin pathway [4,5] (a review on intestinal iron absorption is given in [6,7]). The absorbed iron is then released from the enterocytes to the bloodstream as transferrin-bound iron (TBI) via ferroportin (see below). Under physiological conditions, the bulk of iron enters the cell bound as TBI via transferrin-receptor (TfR) mediated endocytosis followed by endosomal iron liberation. However, resorption of non-transferrin OPEN ACCESSBiomolecules 2015, 5 809 bound iron (NTBI) from the bloodstream may also occur either via DMT-1, the zinc transporter Zip14 (SLC39A14) [8,9] or specific citrate binding sites [10][11][12]. Notably, the serum content of labile NTBI is very low under normal conditions but may rise substantially in diseased states, such as thalassemia, where the high NTBI level-essentially caused by repeated blood transfusion-is considered to cause disease-related oxidative stress [13][14][15][16][17][18]. Similarly, serum ferritin which may serve as iron carrier too [19,20] and is also increased under certain pathological conditions, such as inflammation and cancer [21], can also be endocytosed [22][23][24][25] [34]. Finally, heme-bound iron will enter the cells via HCP1 [1] and tissue macrophages will also "ingest iron" upon phagocytosis of aged cells such as erythrocytes or via the haptoglobin/CD 163 or hemopexin/CD91 mediated uptake of hemoglobin or heme [35] and deliver the recycled iron back to the bloodstream, which is indispensable for the maintenance of systemic iron homeostasis [36].In contrast to several ways of cellular iron uptake, only two mechanisms of cellular iron release are known. Usually, iron release from a cell occurs via ferroportin (Fpn) [37][38][39][40][41] a membrane bound iron exporter, which is controlled by hepatocyte derived hepcidin [42,43], the hepcidin activity itself being regulated by the serine protease matriptase-2 [44,45]. The ferroportin-rel...

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