Iron intracellular pool

In the enterocyte as it enters the absorptive zone near to the villus tips, dietary iron is absorbed either directly as Fe(II) after reduction in the gastrointestinal tract by reductants like ascorbate, or after reduction of Fe(III) by the apical membrane ferrireductase Dcytb, via the divalent transporter Nramp2 (DCT1). Alternatively, haem is taken up at the apical surface, perhaps via a receptor, and is degraded by haem oxygenase to release Fe(II) into the same intracellular pool. The setting of IRPs (which are assumed to act as iron biosensors) determines the amount of iron that is retained within the enterocyte as ferritin, and that which is transferred to the circulation. This latter process is presumed to involve IREG 1 (ferroportin) and the GPI-linked hephaestin at the basolateral membrane with incorporation of iron into apotransferrin. (b) A representation of iron absorption in HFE-related haemochromatosis. 

In the intracellular space, iron is stored as both ferritin (ca. 47%) and haemosiderin (ca. 12%) as well as in the form of an iron-transit pool (ca. 27%). (21) Iron metabolism is of utmost importance for the organism and is characterized by the following values ... 

The transition metals, especially copper and iron ions, catalyse the formation of harmful hydroxyl radicals ( OH) from hydrogen peroxide (Haber-Weiss reaction). Because iron mediates oxidative damage, the substantial intracellular pool of free iron must be regulated by iron chelators, e.g. intracellular storage proteins such as ferritin. 

Although these data provided indirect evidence of iron involvement in ischaemia-reperfusion injury in kidneys and the combined administration of DFX and indomethacin had proved beneficial in actual survival experiments (Gower etal., 1989a), we still felt fhistrated by our inability to generate more direct evidence. At that time, information was just emerging that a small pool of intracellular iron was available in catalytic form as chelates... 

While much is known about siderophore-mediated ferric-iron transport, very little is known about ferrous-iron transport and iron metabolism inside the cell. It is generally assumed that Fe3+ chelated to the siderophore must be reduced to allow removal from the strong claws of the chelator. Indeed, in some cases the siderophore transported iron was found 30 minutes later in the intracellular Fe2+ pool of the cells (Matzanke et ah, 1991). 

Cells contain low concentrations of transition-metal ions, notably iron and copper. For example, the DNA scaffolding protein is reported to contain copper (Lewis and Laemmli 1982). However, no intracellular free copper is detectable (Rae et al. 1999). The intracellular labile iron pool is reported to be around mi-... 

When all the Fe2+ is consumed (the intracellular labile iron pool is around micromolar Epsztejn et al. 1997), the reaction should come to a standstill. In the cellular systems that have been investigated, this seems not to be the case, and it has been postulated that Fe3+ (possibly complexed to DNA) is reduced by H202 in a slow reaction [reaction (49) Ward et al. 1985],... 

Konijn AM, Glickstein H, Vaisman B, et al, The cellular labile iron pool and intracellular ferritin in K562 cells. Blood 1999 94 2128-2134. 

Within the past few years, there has been considerable progress in understanding the role played by the mitochondria in the cellular homeostasis of iron. Thus, erythroid cells devoid of mitochondria do not accumulate iron (7, 8), and inhibitors of the mitochondrial respiratory chain completely inhibit iron uptake (8) and heme biosynthesis (9) by reticulocytes. Furthermore, the enzyme ferrochelatase (protoheme ferro-lyase, EC 4.99.1.1) which catalyzes the insertion of Fe(II) into porphyrins, appears to be mainly a mitochondrial enzyme (10,11,12,13, 14) confined to the inner membrane (15, 16, 17). Finally, the importance of mitochondria in the intracellular metabolism of iron is also evident from the fact that in disorders with deranged heme biosynthesis, the mitochondria are heavily loaded with iron (see Mitochondrial Iron Pool, below). It would therefore be expected that mitochondria, of all mammalian cells, should be able to accumulate iron from the cytosol. From the permeability characteristics of the mitochondrial inner membrane (18) a specialized transport system analogous to that of the other multivalent cations (for review, see Ref. 19) may be expected. The relatively slow development of this field of study, however, mainly reflects the difficulties in studying the chemistry of iron. 

Further therapeutic benefit can be gained by ensuring that the chelating agent is delivered to target sites at an appropriate concentration, rate and duration. Ideally for maximal chelation, a drug must be present within the body at both a reasonable concentration and length of time to ensure interception of iron from either extracellular or intracellular iron pools. Compounds with short plasma half lives are thus likely to be less effective due to the limited pool of chelatable iron present within the body at any one time. 

The predominant class of intracellular iron-storage compounds is represented by ferritin in eukaryotes and bacterioferritin in prokaryotes (see Iron Proteins for Storage Transport their Synthetic Analogs). In various in vivo Mdssbauer spectroscopic studies on siderophore uptake in fungi, it was realized that siderophores can also function as intracellular iron-storage compounds. In the ascomycete Neurospora crassa, the transport siderophore coprogen represents an intracellular transient iron pool. A major part of coprogen-bound iron is transferred to a... 

In addition to hemoproteins, the other major metabolically active pool of intracellular iron is the nonheme iron-sulfur proteins (see Iron-Sulfur Proteins), which function primarily as elecfron carriers, most especially in the mitochondrial electron transfer chain. In vitro treatment with NO has been shown to result in conversion of the iron in these clusters into dinitrosyhron thiol complexes ((RS-)2Fe(NO)2). As described in more detail below, these complexes exhibit a characteristic EPR signal, which has been observed in both NO-producing activated macrophages and their tumor cell targets, suggesting that such complexes may also be formed in vivo. 

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