Ferritin release

Iron is stored in the liver in the form of ferritin. When the level of circulating iron becomes low, ferritin releases iron into the blood. 

The release of iron from ferritin can be induced by different factors. In 1984, Biemond et al. [159] have shown that stimulated leukocytes mobilize iron from human and horse ferritin. Release of iron was induced by superoxide because SOD inhibited this process. Similarly, the release of iron from ferritin can be induced by xanthine oxidase [160] this process is believed to induce ischemia and inflammation. Under anerobic conditions xanthine oxidase is also able to stimulate iron release from ferritin through superoxide-independent mechanism [161]. Another physiological free radical nitric oxide also stimulates iron release from ferritin [162],... 

Figure 1 Release of ferritin (500-kDa protein) from a matrix of EVAc. (a) The cumulative fraction of mass released from matrices containing 35% ( ) or 50% ( ) ferritin by mass is plotted versus time, (b) The same cumulative mass fraction released from the 50% loaded matrices is plotted versus the square root of time. The dashed line represents the fit to the linear model of desorption from a slab, Eq. (5). Data points represent the mean cumulative fraction of mass of ferritin released from four EVAc matrices incubated in buffered saline at 37 °C. The error bars represent 1 SD of the mean. Some error bars are smaller than the symbols.

Xanthine oxidase, mol wt ca 275,000, present in milk, Hver, and intestinal mucosa (131), is required in the cataboHsm of nucleotides. The free bases guanine and hypoxanthine from the nucleotides are converted to uric acid and xanthine in the intermediate. Xanthine oxidase cataly2es oxidation of hypoxanthine to xanthine and xanthine to uric acid. In these processes and in the oxidations cataly2ed by aldehyde oxidase, molecular oxygen is reduced to H2O2 (133). Xanthine oxidase is also involved in iron metaboHsm. Release of iron from ferritin requires reduction of Fe " to Fe " and reduced xanthine oxidase participates in this conversion (133). 

Ferritin, an iron-binding protein, prevents ionized iron (Fe ) from reaching toxic levels within cells. Elemental iron stimulates ferritin synthesis by causing the release of a cytoplasmic protein that binds to a specific region in the 5 nontranslated region of ferritin mRNA. Disruption of this protein-mRNA interaction activates ferritin mRNA and results in its translation. This mechanism provides for rapid control of the synthesis of a protein that sequesters Fe +, a potentially toxic molecule. 

Nitric oxide has also been implicated in PD. Thus animals with MPTP-induced Parkinsonism not only show extensive gliosis in the substantia nigra (like humans) in which the glial cells produce NO, but Liberatore and colleagues have found that in iNOS (inducible nitric oxide synthase) knock-out mice the toxicity of MPTP is halved. Since NO releases iron from ferritin and produces toxic peroxinitrate in the presence of superoxide radicals it could accelerate, even if it does not initiate, dopaminergic cell death (see Hirsch and Hunot 2000 for further details). 

NADH, which enters the Krebs cycle. However, during cerebral ischaemia, metabolism becomes anaerobic, which results in a precipitous decrease in tissue pH to below 6.2 (Smith etal., 1986 Vonhanweh etal., 1986). Tissue acidosis can now promote iron-catalysed free-radical reactions via the decompartmentalization of protein-bound iron (Rehncrona etal., 1989). Superoxide anion radical also has the ability to increase the low molecular weight iron pool by releasing iron from ferritin reductively (Thomas etal., 1985). Low molecular weight iron species have been detected in the brain in response to cardiac arrest. The increase in iron coincided with an increase in malondialdehyde (MDA) and conjugated dienes during the recirculation period (Krause et al., 1985 Nayini et al., 1985). 

The release of iron from intracellular ferritin stores is thought to involve the reduction of Fe to Fe " (Funk et al., 1985) and one would expect this reduction to be fecilitated by the low oxygen tension, increased levels of reducing species and the low pH shown by nuclear magnetic resonance (NM to be as low as 6.9 after only 6 h of cold storage (Fuller et al., 1988). Exogenous redox-active quinones such as adriamycin have been shown to catalyse lipid peroxidation in the presence of ferritin under hypoxic conditions (Vile and Winterbourne, 1988), and lipid peroxidation is stimulated in micro-somes in the presence of purified ferritin and flavin... 

Biemond, P., Swaak, A.J.G., van Eijk, H.G. and Koster, J.F. (1988). Superoxide-dependent iron release from ferritin in inflammatory diseases. Free Rad. Biol. Med. 4, 185-198. 

Microsomal chemiluminescence (lipid peroxidation) is stimulated by oxygenation in the presence of anaerobicaUy released ferritin iron. Fed. Proc. 45, 174. 

Figure 7.5 Model of ferritin (and erythroid a-aminolaevulinate synthase) translation/ribosome binding regulation by IRP. In (a), with IRP not bound to the IRE (1) binding of the 43S preinitiation complex (consisting of the small ribosomal 40S subunit, GTP and Met-tRNAMet) to the mRNA is assisted by initiation factors associated with this complex, as well as additional eukaryotic initiation factors (elFs) that interact with the mRNA to facilitate 43S association. Subsequently (2), the 43S preinitiation complex moves along the 5 -UTR towards the AUG initiator codon, (3) GTP is hydrolysed, initiation factors are released and assembly of the 80S ribosome occurs. Protein synthesis from the open reading frame (ORF) can now proceed. In (b) With IRP bound to the IRE, access of the 43S preinitiation complex to the mRNA is sterically blocked. From Gray and Hentze, 1994, by permission of Oxford University Press.

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. 

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