Ferritin: structure, biosynthesis, and role in iron metabolism.

Munro, Hamish N.; Linder, Maria C.

doi:10.1152/physrev.1978.58.2.317

Cited by 377 publications

(164 citation statements)

References 0 publications

Supporting

Mentioning

158

Contrasting

Order By: Relevance

“…Iron loading of ferritin takes place through symmetrical channels and is supposed to be an autonomous process in response to the concentration of cytosolic iron [9,10]. When iron is required for anabolic purposes, it is released from ferritin, usually in combination with an upregulation of transferrin receptors, increased receptor-mediated iron uptake, and downregulation of ferritin [15].…”

Section: Figure 1 Schematic Illustration Of Cellular Iron-uptake Inmentioning

confidence: 99%

See 1 more Smart Citation

Cell sensitivity to oxidative stress is influenced by ferritin autophagy

Kurz

Gustafsson²,

Brunk

2011

Free Radical Biology and Medicine

View full text Add to dashboard Cite

To test the consequences of lysosomal degradation of differently iron-loaded ferritin molecules and to mimic ferritin autophagy under iron-overload and normal conditions, J774 cells were allowed to endocytose heavily iron-loaded ferritin, probably with some adventitious iron, (Fe-Ft) or iron-free apo-ferritin (apo-Ft). When cells subsequently were exposed to a bolus dose of hydrogen peroxide, apo-Ft prevented lysosomal membrane permeabilization (LMP), while Fe-Ft enhanced LMP. A 4 h pulse of Fe-Ft initially increased oxidative stress-mediated LMP that was reversed after another 3 h at standard culture conditions, suggesting that lysosomal iron is rapidly exported from lysosomes, with resulting upregulation of apo-ferritin that supposedly is autophagocytosed, thereby preventing LMP by binding intra-lysosomal redox-active iron. The obtained data suggest that upregulation of the stress-protein ferritin is a rapid adaptive mechanism that counteracts LMP and ensuing apoptosis during oxidative stress. In addition, prolonged iron starvation was found to induce apoptotic cell death that, interestingly, was preceded by LMP, suggesting that LMP is a more general phenomenon in apoptosis then so far recognized. The findings provide new insights into ageing and neurodegenerative diseases that are associated with enhanced amounts of cellular iron and show that lysosomal iron-loading sensitizes to oxidative stress.

show abstract

Section: Figure 1 Schematic Illustration Of Cellular Iron-uptake Inmentioning

confidence: 99%

“…biomolecules, where it is not accessible to hydrogen peroxide. Additionally, iron can be stored for further use in ferritin, a 450 kD protein that binds up to 4,500 atoms of iron [4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Cell sensitivity to oxidative stress is influenced by ferritin autophagy

Kurz

Gustafsson²,

Brunk

2011

Free Radical Biology and Medicine

View full text Add to dashboard Cite

show abstract

“…Ferritin's key role is highlighted by the following observations. (i) All eukaryotic cells investigated thus far have been shown to express ferritin (4). (ii) Cellular proliferation is dependent on the availability of iron, and ferritin levels are closely regulated during normal proliferation and have been found to be abnormal in various malignancies (5,6).…”

mentioning

confidence: 99%

A cis-acting element is necessary and sufficient for translational regulation of human ferritin expression in response to iron.

Hentze¹,

Rouault²,

Caughman³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

232

112

View full text Add to dashboard Cite

Ferritin plays a key role in determining the intracellular fate of iron and is highly regulated by the iron status of the cell. We have identified a cis-acting element in the transcribed but nontranslated 5' leader sequence of human ferritin heavy-chain mRNA. In transiently transfected murine fibroblasts, the presence of a 157-nucleotide region of the 5' leader sequence was found to be necessary for iron-dependent regulation of ferritin biosynthesis. Further, this 5' leader region is sufficient to transfer iron-mediated translational control to the expression of a heterologous gene product, chloramphenicol acetyltransferase.Ferritin is the major intracellular repository of iron and exists as a heteropolymer of 24 subunits containing both heavy and light chains (1). It serves to sequester and thereby detoxify iron not otherwise utilized for cellular metabolism (2). A more active role of ferritin has been suggested (3), in which iron sequestration may limit and regulate iron availability for cellular metabolism. Ferritin's key role is highlighted by the following observations. (i) All eukaryotic cells investigated thus far have been shown to express ferritin (4). (ii) Cellular proliferation is dependent on the availability of iron, and ferritin levels are closely regulated during normal proliferation and have been found to be abnormal in various malignancies (5, 6). (iii) Ferritin in the cells lining the duodenal mucosa is likely to regulate intestinal iron absorption. Furthermore, since one ofthe most common autosomal recessive disorders, hereditary hemochromatosis, is characterized by pathologically increased absorption of dietary iron, abnormal regulation of ferritin expression or abnormal ferritin function could play a major role in this disorder (7). Thus, the regulation of ferritin levels by iron is the means by which ferritin can both influence and respond to iron homeostasis.It is therefore important to elucidate the mechanisms by which ferritin gene expression is regulated. Munro and his colleagues (8, 9) suggested a translational regulation of ferritin expression in rat liver, based on two observations: (i) actinomycin D does not inhibit the stimulatory effect of iron on ferritin expression and (ii) cytoplasmic ferritin mRNA shifts from an inactive messenger-ribonucleoprotein pool to translationally active polysomes upon iron induction. Similar results were obtained for reticulocytes and liver of bullfrog tadpoles (10, 11). In further support of translational control of ferritin expression, cytoplasmic mRNA levels were shown to remain constant over a wide range of biosynthetic rates induced by iron (9). The recent cloning of the human ferritin heavy-chain cDNA and gene (12)(13)(14)(15) has allowed us to directly address this question of the mechanism of biosynthetic regulation at a molecular level.Previous work showed that a 7.2-kilobase (kb) HindIII genomic DNA fragment (pUCM11) is actively transcribed in stably transformed and transiently transfected murine B6 fibroblasts (13), giving rise to a...

show abstract

“…Ferritin is the major iron-storage protein in eukaryotes (1)(2)(3). Its synthesis is regulated by iron (4)(5)(6)(7)(8).…”

mentioning

confidence: 99%

Translational repression in eukaryotes: partial purification and characterization of a repressor of ferritin mRNA translation.

Walden

Daniels-McQueen

Brown

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

113

View full text Add to dashboard Cite

Mouse and rabbit ferritin mRNAs translate very poorly in rabbit reticulocyte lysates relative to most other mRNAs. This translational deficiency is not seen in wheat germ lysates, suggesting the presence of an inhibitor in reticulocyte lysate that is specific for ferritin mRNA. A specific repressor of ferritin mRNA translation has been partially purified from rabbit reticulocytes by differential ultracentrifugation, ammonium sulfate fractionation, and chromatography on phosphocellulose, DEAE-cellulose, and Sephacryl S-300. The elution profile from the latter suggests an aggregate molecular mass of 180 kDa for the repressor. The inhibitory activity of this repressor against native ferritin mRNA can be relieved by adding in vitro transcripts of ferritin light-chain RNAs that contain the first 92 nucleotides of the 5' untranslated region. No other sequences appear to be necessary for this effect.Ferritin is the major iron-storage protein in eukaryotes (1-3). Its synthesis is regulated by iron (4-8). Early evidence suggested that the primary site of this regulation may be translational (4)(5)(6)(7)(8)(9). This has been confirmed recently by the discovery of the "iron-responsive element" (IRE), a highly conserved sequence of 28 nucleotides, in the 5' untranslated region (5' UTR) of all ferritin mRNAs (10-13). The presence of this sequence renders the translation of downstream open reading frames (ORFs) responsive to the iron status of the cell. It seems likely that iron does not interact directly with the IRE, but rather that its effects are mediated by one or more "repressors." These substances would be expected (i) to bind specifically to the IRE sequence within the mRNA and (ii) to be sensitive to intracellular iron pools.In this communication we describe the identification and partial purification of one such repressor, an ==180-kDa complex composed primarily, if not exclusively, of protein.Its distinctive feature is that it inhibits translation of both light-and heavy-chain (L and H) ferritin mRNAs in a wheat germ lysate with a high degree of specificity. Moreover, this inhibition can be relieved by the addition of short RNA transcripts containing the IRE sequence. No other region of the L ferritin mRNA sequence is required for this effect, suggesting that the repressor recognizes the IRE specifically.

show abstract

Ferritin: structure, biosynthesis, and role in iron metabolism.

Cited by 377 publications

References 0 publications

Cell sensitivity to oxidative stress is influenced by ferritin autophagy

Cell sensitivity to oxidative stress is influenced by ferritin autophagy

A cis-acting element is necessary and sufficient for translational regulation of human ferritin expression in response to iron.

Translational repression in eukaryotes: partial purification and characterization of a repressor of ferritin mRNA translation.

Contact Info

Product

Resources

About