Ferritin: a novel mechanism for delivery of iron to the brain and other organs

Fisher, Jerron Lee; Devraj, Kavi; Ingram, Justin; Slagle‐Webb, Becky; Madhankumar, A.; Liu, Xaioli; Klinger, Marianne; Simpson, Ian A.; Connor, James R.

doi:10.1152/ajpcell.00599.2006

Cited by 186 publications

(146 citation statements)

References 46 publications

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“…We therefore suggest that serum ferritin is not a major pathway of systemic iron transport, but locally secreted ferritins may play such a role in selected tissues. 16,47,48 Both kidney and macrophage ferritins are rich in H-subunits ( Figure 5A and not shown), and ferritin secreted from macrophages contains iron ( Figure 6D). Thus, H-subunit containing heteropolymers could be selectively and locally removed by H-subunit-specific receptors for ferritin, such as TIM-2, and the residual ferritin, containing mostly L-subunits, few H-subunits and little iron would remain in the blood stream.…”

Section: Iron In Serum Ferritinmentioning

confidence: 99%

Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway

Cohen

Gutiérrez

Weiss

et al. 2010

Blood

386

324

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The serum ferritin concentration is a clinical parameter measured widely for the differential diagnosis of anemia. Its levels increase with elevations of tissue iron stores and with inflammation, but studies on cellular sources of serum ferritin as well as its subunit composition, degree of iron loading and glycosylation have given rise to conflicting results. To gain further understanding of serum ferritin, we have used traditional and modern methodologies to characterize mouse serum ferritin. We find that both splenic macrophages and proximal tubule cells of the kidney are possible cellular sources for serum ferritin and that serum ferritin is secreted by cells rather than being the product of a cytosolic leak from damaged cells. Mouse serum ferritin is composed mostly of L-subunits, whereas it contains few H-subunits and iron content is low. L-subunits of serum ferritin are frequently truncated at the C-terminus, giving rise to a characteristic 17-kD band that has been previously observed in lysosomal ferritin. Taken together with the fact that mouse serum ferritin is not detectably glycosylated, we propose that mouse serum ferritin is secreted through the nonclassical lysosomal secretory pathway. (Blood. 2010;116(9):1574-1584) IntroductionFerritin in mammals is a mostly intracellular, cytosolic iron storage and detoxification protein. It consists of H-and L-subunits that assemble into a 24-subunit hollow sphere in which iron is sequestered. 1 However, ferritin can also be detected extracellularly, in cerebrospinal fluid and sinovial fluid. In serum it is an extracellular ferritin that has been used extensively in diagnostic tests. In the clinical setting, serum ferritin evaluation is most commonly used to estimate body iron stores as low serum ferritin correlates with iron depletion, whereas high serum ferritin correlates with elevated body iron stores or with inflammation in patients with normal body iron stores. 2,3 Characterization of serum ferritin has produced many controversial results regarding subunit composition, iron content and other features. It has been compared in some studies to the "natural apoferritin" fraction found in many tissues, which is essentially devoid of iron 4 while other studies have claimed that serum ferritin contains considerable amounts of iron. 5 In insects, ferritin is a secreted protein composed of 2 types of subunits and the heteropolymer functions most likely as an iron transporter in the hemolymph. Each of the subunits has a classical secretion signal and ferritin is secreted from the insect fat body. 6 In contrast, mammalian H-and L-ferritin subunits lack signals mediating endoplasmic reticulum (ER) targeting, but ferritin can traffic to the lysosomal compartment through autophagy. 7 Binding of human serum ferritin to the lectin Concanavalin A (ConA) has previously suggested that ferritin is glycosylated 8,9 and actively secreted through the ER-Golgi pathway. 10 Indeed, it was shown in hepatocyte cell-models that inhibition of ER-Golgi trafficking abolished secretion o...

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Section: Iron In Serum Ferritinmentioning

confidence: 99%

Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway

Cohen

Gutiérrez

Weiss

et al. 2010

Blood

386

324

View full text Add to dashboard Cite

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“…Herein, HoS-apoferritin (horse spleen apoferritin, 85 % and 15% L and H chains, respectively) is investigated for the simultaneous delivery of therapeutic and imaging agents (loaded into its internal cavity) to breast cancer cells by exploiting the L-ferritin transporting route without any further chemical functionalization of the protein surface. In fact, although L-ferritin functions are traditionally associated with intracellular iron storage, additional functions related to iron delivery based on a transferrinindependent mechanism, to different target organs such as brain, liver and spleen have been recently discovered and investigated 13 . The involved receptors belong to the scavenger receptor class A member 5 (SCARA5) 14 for L-ferritin and to TIM-2 15 and TfR-1 11 for H-ferritin, respectively.…”

Section: Introductionmentioning

confidence: 99%

Targeting ferritin receptors for the selective delivery of imaging and therapeutic agents to breast cancer cells

et al. 2015

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Abstract. In this work the selective uptake of native horse spleen-ferritin and apoferritin loaded with MRI contrast agents have been assessed on human breast cancer cells (MCF-7, MDA-MB-231). The higher expression of L-ferritin receptors (SCARA5) let to an enhanced uptake in MCF-7 as shown in T2 and T1 weighted MR images, respectively. The high efficiency of ferritin internalization in MCF-7 has been exploited for the simultaneous delivery of curcumin, a natural therapeutic molecule endowed with antineoplastic and anti-inflammatory action, and the MRI contrast agent GdHPDO3A. This theranostic system is able to treat selectively breast cancer cells over-expressing ferritin receptors. By entrapping in apoferritin both Gd-HPDO3A and curcumin was possible to deliver a therapeutic dose of 97 g/ml (as calculated by MRI) of this natural drug into MCF-7 cells, obtaining a significant reduction of cell proliferation.Introduction.

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“…The average number of iron atoms per ferritin varies from zero to up to 4,000, averaging 1,000 -1,500 (30,52). Specific ferritin binding has been identified in a number of cells and tissues, including liver, placenta, and hepatoma and lymphoid, erythroid, and endothelium cells (1,7,35,41,48). In some cell types, binding of ferritin is followed by internalization.…”

mentioning

confidence: 99%

Endocytic pathway of exogenous iron-loaded ferritin in intestinal epithelial (Caco-2) cells

Antileo

Garri

Tapia

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Artículo de publicación ISIFerritin, a food constituent of animal and vegetal origin, is a source of dietary iron. Its hollow central cavity has the capacity to store up to 4,500 atoms of iron, so its potential as an iron donor is advantageous to heme iron, present in animal meats and inorganic iron of mineral or vegetal origin. In intestinal cells, ferritin internalization by endocytosis results in the release of its iron into the cytosolic labile iron pool. The aim of this study was to characterize the endocytic pathway of exogenous ferritin absorbed from the apical membrane of intestinal epithelium Caco-2 cells, using both transmission electron microscopy and fluorescence confocal microscopy. Confocal microscopy revealed that endocytosis of exogenous AlexaFluor 488-labeled ferritin was initiated by its engulfment by clathrin-coated pits and internalization into early endosomes, as determined by codistribution with clathrin and early endosome antigen 1 (EEA1). AlexaFluor 488-labeled ferritin also codistributed with the autophagosome marker microtubule-associated protein 1 light chain 3 (LC3) and the lysosome marker lysosomal-associated membrane protein 2 (LAMP2). Transmission electron microscopy revealed that exogenously added ferritin was captured in plasmalemmal pits, double-membrane compartments, and multivesicular bodies considered as autophagosomes and lysosomes. Biochemical experiments revealed that the lysosome inhibitor chloroquine and the autophagosome inhibitor 3-methyladenine (3-MA) inhibited degradation of exogenously added 131I-labeled ferritin. This evidence is consistent with a model in which exogenous ferritin is internalized from the apical membrane through clathrin-coated pits, and then follows a degradation pathway consisting of the passage through early endosomes, autophagosomes, and autolysosomes.This work was financed by project ICM-P05-001-F from the Millennium Scientific Initiative, Ministerio de Economía, Chile (to M. T. Núñez), and by Grants 1070840 from Fondo Nacional de Ciencia y Tecnología (to M. T. Núñez) and ACT 1111 (to S. Lavandero and M. Chiong)

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Ferritin: a novel mechanism for delivery of iron to the brain and other organs

Abstract: IA, Connor JR. Ferritin: a novel mechanism for delivery of iron to the brain and other organs.

Cited by 186 publications

References 46 publications

Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway

Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway

Targeting ferritin receptors for the selective delivery of imaging and therapeutic agents to breast cancer cells

Endocytic pathway of exogenous iron-loaded ferritin in intestinal epithelial (Caco-2) cells

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