Iron release from haemosiderin and ferritin by therapeutic and physiological chelators.
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ABSTRACT:
SUBMITTER: O'Connell MJ
PROVIDER: S-EPMC1138761 | biostudies-other | 1989 Jun
REPOSITORIES: biostudies-other
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Project description:The heteroaromatic chelators 1,2-dimethyl-3-hydroxypyrid-4-one, maltol, mimosine and 2,4-dihydroxypyridine-N-oxide, have been shown to mobilize iron from human spleen haemosiderin, ferritin and also from iron(III) precipitates, all containing equal amounts of iron, at physiological pH. In the case of almost every chelator, the least-solubilized polynuclear iron form was ferritin, whereas haemosiderin was more soluble and the iron(III) precipitate the most soluble of all. Most of the chelators were more efficient than desferrioxamine at releasing iron from ferritin, but less efficient in the removal of iron from the other two polynuclear iron forms. It is suggested that the chelator differences in iron mobilization may be related to variations in the chelator molecular structure, the protein structure, iron forms and in the mechanism of iron release.
| S-EPMC1147528 | biostudies-other
Project description:Deferoxamine (DFO) is a high-affinity Fe (III) chelator produced by Streptomyces pilosus. DFO is used clinically to remove iron from patients with iron overload disorders. Orally administered DFO cannot be absorbed, and therefore it must be injected. Here we show that DFO induces ferritin degradation in lysosomes through induction of autophagy. DFO-treated cells show cytosolic accumulation of LC3B, a critical protein involved in autophagosomal-lysosomal degradation. Treatment of cells with the oral iron chelators deferriprone and desferasirox did not show accumulation of LC3B, and degradation of ferritin occurred through the proteasome. Incubation of DFO-treated cells with 3-methyladenine, an autophagy inhibitor, resulted in degradation of ferritin by the proteasome. These results indicate that ferritin degradation occurs by 2 routes: a DFO-induced entry of ferritin into lysosomes and a cytosolic route in which iron is extracted from ferritin before degradation by the proteasome.
| S-EPMC2777130 | biostudies-literature
Project description:Several alpha-oxohydroxy heteroaromatic chelators have been shown to mobilize iron from horse spleen ferritin. Although the reactions were slow, taking up to 3 days to reach completion, the amounts of iron mobilized were higher than those reported for other chelators. These results increase the prospects for the clinical use of alpha-oxohydroxy chelators in the treatment of iron overload.
| S-EPMC1153022 | biostudies-other
Project description:BackgroundBacterial infections involving multidrug-resistant Gram-negative bacteria have become critically involved in the current antibiotic crisis. This, together with the bacterial evolution ability, prioritizes the discovery of new antibiotics. Research on microbial iron acquisition pathways and metabolites, particularly siderophores, has highlighted hopeful aspects for the design of advanced antimicrobial approaches. Moreover, exploiting siderophores machinery to treat diseases associated with iron overload and cancer is of additional interest for the therapeutic arena.Aim of reviewThis review highlights and provides a renewed perspective on the evolutionary path of siderophores, from primordial siderophores to new iron chelating agents, stimulating the field to build on the past and shape the future.Key scientific concepts of reviewThe effectiveness of siderophore-mimicking antibiotics appears to be high and selective for Gram-negative pathogens, rendering multidrug-resistant (MDR) bacteria susceptible to killing. Herein, cefiderocol, a new siderophore antibiotic, is well positioned in the clinic to treat MDR infections instigated by Gram-negative bacteria, particularly urinary tract infections and pneumonia. This siderophore has a mode of action based on a "Trojan horse" strategy, using the iron uptake systems for efficient bacterial penetration and killing. Recent progress has also been achieved concerning new iron chelating compounds to treat diseases associated with iron overload and cancer. Though these compounds still face great challenges for a clinical application, their promising results open up new doors for the design and development of innovative iron chelating compounds, taking benefit from the structurally diverse nature of siderophores.
| S-EPMC9263657 | biostudies-literature
Project description:1. Ferritin and haemosiderin in diluted tissue cannot be quantitatively separated by centrifugation unless the pH is brought below 6. 2. These iron-storage substances can be separated from one another and from haemoglobin by ion-exchange chromatography on CM-cellulose, when good recoveries of total tissue iron are obtained. 3. The ferritin fraction has been identified by its solubility, its appearance under the electron microscope, crystallization with Cd(2+) and the fact that it corresponds quantitatively to the heat-stable portion of the tissue non-haem iron.
| S-EPMC1215205 | biostudies-other
Project description:Ferritin and haemosiderin were shown, by the measurement of malondialdehyde production and loss of polyunsaturated fatty acids, to stimulate lipid peroxidation in liposomes. At pH 7.4 ascorbate was additionally required to achieve peroxidation; however, peroxidation occurred at pH 4.5 in the presence of iron-proteins alone. The damage was completely inhibited by the incorporation of chain-breaking antioxidants (alpha-tocopherol and butylated hydroxytoluene) into the liposomes. Metal chelators (desferrioxamine and EDTA) also completely inhibited lipid peroxidation. These and further results indicate that, at pH 4.5, even in the absence of a reducing agent, iron is released from haemosiderin and can mediate oxidative damage to a lipid membrane.
| S-EPMC1145159 | biostudies-other
Project description:Isolated haemosiderin contained iron and nitrogen in a weight ratio of 6.75, with phosphorus and no detectable haem. Considerably more iron was released from haemosiderin under acidic conditions than under neutral conditions in the presence of ascorbate, nitrilotriacetate or dithionite. Unlike the situation with ascorbate, chelators such as citrate, ADP or succinate induced the release of only some iron, with almost no pH-dependence. Dehydroascorbate (the oxidized form of ascorbate with no reducing capacity) behaved like citrate, ADP, succinate or desferal, rather than like ascorbate itself, in releasing iron. GSH had less effect on the release of iron than these chelators, but in the presence of a small amount of chelator the release of iron increased, especially under acidic conditions. Thus reduction, chelation and pH were all found to be important factors involved in the release of iron from haemosiderin. Investigation by e.p.r. of hydroxyl-radical production by the released iron showed high radical productivity at an acidic pH. However, at a physiological pH, almost no radical formation was detected, except in the presence of nitrilotriacetate. These findings suggested that, under physiological conditions, haemosiderin was not an effective iron donor and was almost not involved in radical production. Under acidic conditions, however, such as in inflammation, hypoxia and in a lysosomal milieu, it could possibly be an iron donor and is thought to be implicated in radical production and tissue damage in iron-overloaded conditions.
| S-EPMC1148895 | biostudies-other
Project description:Ferritins are highly conserved supramolecular protein nanostructures composed of two different subunit types, H (heavy) and L (light). The two subunits co-assemble into a 24-subunit heteropolymer, with tissue specific distributions, to form shell-like protein structures within which thousands of iron atoms are stored as a soluble inorganic ferric iron core. In-vitro (or in cell free systems), the mechanisms of iron(II) oxidation and formation of the mineral core have been extensively investigated, although it is still unclear how iron is loaded into the protein in-vivo. In contrast, there is a wide spread belief that the major pathway of iron mobilization from ferritin involves a lysosomal proteolytic degradation of ferritin, and the dissolution of the iron mineral core. However, it is still unclear whether other auxiliary iron mobilization mechanisms, involving physiological reducing agents and/or cellular reductases, contribute to the release of iron from ferritin. In vitro iron mobilization from ferritin can be achieved using different reducing agents, capable of easily reducing the ferritin iron core, to produce soluble ferrous ions that are subsequently chelated by strong iron(II)-chelating agents. Here, we review our current understanding of iron mobilization from ferritin by various reducing agents, and report on recent results from our laboratory, in support of a mechanism that involves a one-electron transfer through the protein shell to the iron mineral core. The physiological significance of the iron reductive mobilization from ferritin by the non-enzymatic FMN/NAD(P)H system is also discussed.
| S-EPMC6315955 | biostudies-literature
Project description:A minor electrophoretically fast component was found in ferritin from iron-loaded rat liver in addition to a major electrophoretically slow ferritin similar to that observed in control rats. The electrophoretically fast ferritin showed immunological identity with the slow component, but on electrophoresis in SDS it gave a peptide of 17.3 kDa, in contrast with the electrophoretically slow ferritin, which gave a major band corresponding to the L-subunit (20.7 kDa). Thus the electrophoretically fast ferritin resembles that reported by Massover [(1985) Biochim. Biophys. Acta 829, 377-386] in livers of mice with short-term parenteral iron overload. The electrophoretically fast ferritin had a lower iron content (2000 Fe atoms/molecule) than the electrophoretically slow ferritin (3000 Fe atoms/molecule). Removal and re-incorporation of iron was possible without effect on the electrophoretic mobility of either ferritin species. On subcellular fractionation the electrophoretically fast ferritin was enriched in pellet fractions and was the sole soluble ferritin isolated from iron-laden secondary lysosomes (siderosomes). The amount and relative proportion of the electrophoretically fast species increased with iron loading. Haemosiderin isolated from siderosomes was found to contain a peptide reactive to anti-ferritin serum and corresponding to the 17.3 kDa peptide of the electrophoretically fast ferritin species. Unlike the electrophoretically slow ferritin, the electrophoretically fast ferritin did not become significantly radioactive in a 1 h biosynthetic labelling experiment. We conclude that the minor ferritin is not, as has been suggested for mouse liver ferritin, 'a completely new species of smaller holoferritin that represents a shift in the ferritin phenotype' in response to siderosis, but a precursor of haemosiderin, in agreement with the proposal by Richter [(1984) Lab. Invest. 50, 26-35] concerning siderosomal ferritin.
| S-EPMC1148141 | biostudies-other
Project description:Here, we report the synthesis, characterization, and efficacy study of Fe/Fe₃O₄-nanoparticles that were co-labeled with a tumor-homing and membrane-disrupting oligopeptide and the iron-chelator Dp44mT, which belongs to the group of the thiosemicarbazones. Dp44mT and the peptide sequence PLFAERL(D[KLAKLAKKLAKLAK])CGKRK were tethered to the surface of Fe/Fe₃O₄ core/shell nanoparticles by utilizing dopamine-anchors. The 26-mer contains two important sequences, which are the tumor targeting peptide CGKRK, and D[KLAKLAK]₂, known to disrupt the mitochondrial cell walls and to initiate programmed cell death (apoptosis). It is noteworthy that Fe/Fe₃O₄ nanoparticles can also be used for MRI imaging purposes in live mammals. In a first step of this endeavor, the efficacy of this nanoplatform has been tested on the highly metastatic 4T1 breast cancer cell line. At the optimal ratio of PLFAERD[KLAKLAK]₂CGKRK to Dp44mT of 1 to 3.2 at the surface of the dopamine-coated Fe/Fe₃O₄-nanocarrier, the IC50 value after 24 h of incubation was found to be 2.2 times lower for murine breast cancer cells (4T1) than for a murine fibroblast cell line used as control. Based on these encouraging results, the reported approach has the potential of leading to a new generation of nanoplatforms for cancer treatment with considerably enhanced selectivity towards tumor cells.
| S-EPMC5618274 | biostudies-literature