Ferritin

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Ferritin
Ferritin.png
Structure of the murine ferritin complex [1]
Identifiers
SymbolFerritin
Pfam PF00210
Pfam clan CL0044
InterPro IPR008331
SCOP2 1fha / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
ferritin, light polypeptide
Identifiers
Symbol FTL
NCBI gene 2512
HGNC 3999
OMIM 134790
RefSeq NM_000146
UniProt P02792
Other data
Locus Chr. 19 q13.3–13.4
Search for
Structures Swiss-model
Domains InterPro
ferritin, heavy polypeptide 1
Identifiers
Symbol FTH1
Alt. symbolsFTHL6
NCBI gene 2495
HGNC 3976
OMIM 134770
RefSeq NM_002032
UniProt P02794
Other data
Locus Chr. 11 q13
Search for
Structures Swiss-model
Domains InterPro
ferritin mitochondrial
Mitochondrial Ferritin.png
Crystallographic structure of mitochondrial ferritin. [2]
Identifiers
SymbolFTMT
NCBI gene 94033
HGNC 17345
OMIM 608847
RefSeq NM_177478
UniProt Q8N4E7
Other data
Locus Chr. 5 q23.1
Search for
Structures Swiss-model
Domains InterPro

Ferritin is a universal intracellular and extracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary intracellular iron-storage protein in both prokaryotes and eukaryotes, keeping iron in a soluble and non-toxic form. In humans, it acts as a buffer against iron deficiency and iron overload. [3]

Contents

Ferritin is found in most tissues as a cytosolic protein, but small amounts are secreted into the serum where it functions as an iron carrier. Plasma ferritin is also an indirect marker of the total amount of iron stored in the body; hence, serum ferritin is used as a diagnostic test for iron-deficiency anemia and iron overload. [4] Aggregated ferritin transforms into a water insoluble, crystalline and amorphous form of storage iron called hemosiderin. [5]

Ferritin is a globular protein complex consisting of 24 protein subunits forming a hollow sphereical nanocage with multiple metal–protein interactions. [6] Ferritin with iron removed is called apoferritin. [7] : e10 

Gene

Ferritin genes are highly conserved between species. All vertebrate ferritin genes have three introns and four exons. [8] In human ferritin, introns are present between amino acid residues 14 and 15, 34 and 35, and 82 and 83; in addition, there are one to two hundred untranslated bases at either end of the combined exons. [9] The tyrosine residue at amino acid position 27 is thought to be associated with biomineralization. [10]

Protein structure

Ferritin is a hollow globular protein of mass 474  kDa and comprising 24 subunits. Typically it has internal and external diameters of about 8 and 12 nm, respectively. [11] The nature of these subunits varies by class of organism:

All the aforementioned ferritins are similar, in terms of their primary sequence, with the vertebrate H-type. [12] In E. coli, a 20% similarity to human H-ferritin is observed. [12] Some ferritin complexes in vertebrates are hetero-oligomers of two highly related gene products with slightly different physiological properties. The ratio of the two homologous proteins in the complex depends on the relative expression levels of the two genes.

Cytosolic ferritin shell (apoferritin) is a heteropolymer of 24 subunits of heavy (H) and light (L) peptides that form a hollow spherical nanocage that covers an iron core composed of crystallites together with phosphate and hydroxide ions. The resulting particle is similar to ferrihydrite (5Fe2O3·9H2O). Each ferritin complex can store about 4500 iron (Fe3+) ions. [9] [12] The proportion of H to L subunits varies in ferritin from different tissues, explaining its heterogeneity on isoelectric focusing. L-rich ferritins (from spleen and liver) are more basic than H-rich ferritins (from heart and red blood cells).

Serum ferritin, which is typically iron-poor, consists almost exclusively of L subunits. Serum ferritin is heterogeneous due to glycosylation. The glycosylation and direct relationship of serum ferritin concentration to iron storage in macrophages suggest it is secreted by macrophages in response to changing iron levels.

Human mitochondrial ferritin , MtF, was found to express as a pro-protein. [14] When a mitochondrion takes it up, it processes it into a mature protein similar to the ferritins found in the cytoplasm, which it assembles to form functional ferritin shells. Unlike other human ferritins, it is a homoplymer of H type ferritin and appears to have no introns (intronless) in its genetic code. The mitochondrial ferritin's Ramachandran plot [15] shows its structure to be mainly alpha helical with a low prevalence of beta sheets. It accumulates in large amounts in the erythroblasts of subjects with impaired heme synthesis.

Function

Iron storage

Iron uptake through the 3-fold channel of ferritin Ferritin 3foldchannel.png
Iron uptake through the 3-fold channel of ferritin

Ferritin is present in every cell type. [9] It serves to store iron in a non-toxic form, to deposit it in a safe form, and to transport it to areas where it is required. [16] The function and structure of the expressed ferritin protein varies in different cell types. This is controlled primarily by the amount and stability of messenger RNA (mRNA), but also by changes in how the mRNA is stored and how efficiently it is transcribed. [9] One major trigger for the production of many ferritins is the mere presence of iron; [9] an exception is the yolk ferritin of Lymnaea sp., which lacks an iron-responsive unit. [12]

Free iron is toxic to cells as it acts as a catalyst in the formation of free radicals from reactive oxygen species via the Fenton reaction. [17] Hence vertebrates have an elaborate set of protective mechanisms to bind iron in various tissue compartments[ discuss ]. Within cells, iron is stored in a protein complex as ferritin or the related complex hemosiderin. Apoferritin binds to free ferrous iron and stores it in the ferric state. As ferritin accumulates within cells of the reticuloendothelial system, protein aggregates are formed as hemosiderin. Iron in ferritin or hemosiderin can be extracted for release by the RE cells, although hemosiderin is less readily available. Under steady-state conditions, the level of ferritin in the blood serum correlates with total body stores of iron; thus, the serum ferritin FR5Rl is the most convenient laboratory test to estimate iron stores.[ citation needed ]

Because iron is an important mineral in mineralization, ferritin is employed in the shells of organisms such as molluscs to control the concentration and distribution of iron, thus sculpting shell morphology and colouration. [18] [19] It also plays a role in the haemolymph of the polyplacophora, where it serves to rapidly transport iron to the mineralizing radula. [20]

Iron is released from ferritin for use by ferritin degradation, which is performed mainly by lysosomes. [21]

Ferroxidase activity

Vertebrate ferritin consists of two or three subunits which are named based on their molecular weight: L "light", H "heavy", and M "middle" subunits. The M subunit has only been reported in bullfrogs. In bacteria and archaea, ferritin consists of one subunit type. [22] H and M subunits of eukaryotic ferritin and all subunits of bacterial and archaeal ferritin are H-type and have ferroxidase activity, which means they are able to convert iron from the ferrous (Fe2+) to ferric (Fe3+) forms. This limits the deleterious reaction which occurs between ferrous iron and hydrogen peroxide known as the Fenton reaction which produces the highly damaging hydroxyl radical. The ferroxidase activity occurs at a diiron binding site in the middle of each H-type subunits. [22] [23] After oxidation of Fe(II), the Fe(III) product stays metastably in the ferroxidase center and is displaced by Fe(II), [23] [24] a mechanism that appears to be common among ferritins of all three domains of life. [22] The light chain of ferritin has no ferroxidase activity but may be responsible for the electron transfer across the protein cage. [25]

Immune response

Ferritin concentrations increase drastically in the presence of an infection or cancer. Endotoxins are an up-regulator of the gene coding for ferritin, thus causing the concentration of ferritin to rise. By contrast, organisms such as Pseudomonas, although possessing endotoxin, cause plasma ferritin levels to drop significantly within the first 48 hours of infection. Thus, the iron stores of the infected body are denied to the infective agent, impeding its metabolism. [26]

Stress response

The concentration of ferritin has been shown to increase in response to stresses such as anoxia, [27] which implies that it is an acute phase protein. [28]

Mitochondria

Mitochondrial ferritin has many roles pertaining to molecular function. It participates in ferroxidase activity, binding, iron ion binding, oxidoreductase activity, ferric iron binding, metal ion binding as well as transition metal binding. Within the realm of biological processes it participates in oxidation-reduction, iron ion transport across membranes and cellular iron ion homeostasis.[ citation needed ]

Yolk

In some snails, the protein component of the egg yolk is primarily ferritin. [29] This is a different ferritin, with a different genetic sequence, from the somatic ferritin. It is produced in the midgut glands and secreted into the haemolymph, whence it is transported to the eggs. [29]

Tissue distribution

In vertebrates, ferritin is usually found within cells, although it is also present in smaller quantities in the plasma. [26]

Diagnostic uses

Serum ferritin levels are measured in medical laboratories as part of the iron studies workup for iron-deficiency anemia. [6] They are measured in nanograms per milliliter (ng/mL) or micrograms per liter (μg/L); the two units are equivalent.

The ferritin levels measured usually have a direct correlation with the total amount of iron stored in the body. However, ferritin levels may be artificially high in cases of anemia of chronic disease, where ferritin is elevated in its capacity as an inflammatory acute phase protein and not as a marker for iron overload.[ citation needed ]

Normal ranges

A normal ferritin blood level, referred to as the reference interval is determined by many testing laboratories. The ranges for ferritin can vary between laboratories but typical ranges would be between 40 and 300 ng/mL (=μg/L) for males, and 20–200 ng/mL (=μg/L) for females. [30]

Normal ferritin blood levels according to sex and age[ citation needed ]
Adult males40–300 ng/mL (μg/L) [30]
Adult females20–200 ng/mL (μg/L) [30]
Children (6 months to 15 years)50–140 ng/mL (μg/L)
Infants (1 to 5 months)50–200 ng/mL (μg/L)
Neonates25–200 ng/mL (μg/L)

Deficiency

According to a 2014 review in the New England Journal of Medicine stated that a ferritin level below 30 ng/mL indicates iron deficiency, while a level below 10 ng/mL indicates iron-deficiency anemia. [30] A 2020 World Health Organization guideline states that ferritin indicates iron deficiency below 12 ng/mL in apparently-healthy children under 5 and 15 ng/mL in apparently-healthy individuals of 5 and over. [31]

Some studies suggest that women with fatigue and ferritin below 50 ng/mL see reduced fatigue after iron supplementation. [32] [33]

In the setting of anemia, low serum ferritin is the most specific lab finding for iron-deficiency anemia. [34] However it is less sensitive, since its levels are increased in the blood by infection or any type of chronic inflammation, [35] and these conditions may convert what would otherwise be a low level of ferritin from lack of iron, into a value in the normal range. For this reason, low ferritin levels carry more information than those in the normal range. A falsely low blood ferritin (equivalent to a false positive test) is very uncommon, [35] but can result from a hook effect of the measuring tools in extreme cases. [36]

Low ferritin may also indicate hypothyroidism, [37] vitamin C deficiency or celiac disease.[ citation needed ]

Low serum ferritin levels are seen in some patients with restless legs syndrome, not necessarily related to anemia, but perhaps due to low iron stores short of anemia. [38] [39]

Vegetarianism is not a cause of low serum ferritin levels, according to the American Dietetic Association's position in 2009: "Incidence of iron-deficiency anemia among vegetarians is similar to that of non-vegetarians. Although vegetarian adults have lower iron stores than non-vegetarians, their serum ferritin levels are usually within the normal range." [40]

Excess

If ferritin is high, there is iron in excess or else there is an acute inflammatory reaction in which ferritin is mobilized without iron excess. For example, ferritins may be high in infection without signaling body iron overload.

Ferritin is also used as a marker for iron overload disorders, such as hemochromatosis or hemosiderosis. Adult-onset Still's disease, some porphyrias, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome are diseases in which the ferritin level may be abnormally raised.

As ferritin is also an acute-phase reactant, it is often elevated in the course of disease. A normal C-reactive protein can be used to exclude elevated ferritin caused by acute phase reactions. [ citation needed ]

Ferritin has been shown to be elevated in some cases of COVID-19 and may correlate with worse clinical outcome. [41] [42] Ferritin and IL-6 are considered to be possible immunological biomarkers for severe and fatal cases of COVID-19. Ferritin and C-reactive protein may be possible screening tools for early diagnosis of systemic inflammatory response syndrome in cases of COVID-19. [43] [44]

According to a study of anorexia nervosa patients, ferritin can be elevated during periods of acute malnourishment, perhaps due to iron going into storage as intravascular volume and thus the number of red blood cells falls. [45]

Another study suggests that due to the catabolic nature of anorexia nervosa, isoferritins may be released. Furthermore, ferritin has significant non-storage roles within the body, such as protection from oxidative damage. The rise of these isoferritins may contribute to an overall increase in ferritin concentration. The measurement of ferritin through immunoassay or immunoturbidimeteric methods may also be picking up these isoferritins thus not a true reflection of iron storage status. [46]

Studies reveal that a transferrin saturation (serum iron concentration ÷ total iron binding capacity) over 60 percent in men and over 50 percent in women identified the presence of an abnormality in iron metabolism (hereditary hemochromatosis, heterozygotes, and homozygotes) with approximately 95 percent accuracy. This finding helps in the early diagnosis of hereditary hemochromatosis, especially while serum ferritin still remains low. The retained iron in hereditary hemochromatosis is primarily deposited in parenchymal cells, with reticuloendothelial cell accumulation occurring very late in the disease. This is in contrast to transfusional iron overload in which iron deposition occurs first in the reticuloendothelial cells and then in parenchymal cells. This explains why ferritin levels remain relative low in hereditary hemochromatosis, while transferrin saturation is high. [47] [48]

In chronic liver diseases

Hematological abnormalities often associate with chronic liver diseases. Both iron overload and iron deficient anemia have been reported in patients with liver cirrhosis. [49] [50] The former is mainly due to reduced hepcidin level caused by the decreased synthetic capacity of the liver, while the latter is due to acute and chronic bleeding caused by portal hypertension. Inflammation is also present in patients with advanced chronic liver disease. As a consequence, elevated hepatic and serum ferritin levels are consistently reported in chronic liver diseases. [51] [52] [53]

Studies showed association between high serum ferritin levels and increased risk of short-term mortality in cirrhotic patients with acute decompensation [54] and acute-on-chronic liver failure. [55] An other study found association between high serum ferritin levels and increased risk of long-term mortality in compensated and stable decompensated cirrhotic patients. [56] The same study demonstrated that increased serum ferritin levels could predict the development of bacterial infection in stable decompensated cirrhotic patients, while in compensated cirrhotic patients the appearance of the very first acute decompensation episode showed higher incidence in patients with low serum ferritin levels. This latter finding was explaind by the association between chronic bleeding and increased portal pressure. [56]

Discovery

Ferritin was discovered in 1937 by the Czechoslovakian scientist Vilém Laufberger  [ cs ]. [57] [7] : e9  Sam Granick and Leonor Michaelis produced apoferritin in 1942 [7] : e10 

Applications

Ferritin is used in materials science as a precursor in making iron nanoparticles for carbon nanotube growth by chemical vapor deposition.

Cavities formed by ferritin and mini-ferritins (Dps) proteins have been successfully used as the reaction chamber for the fabrication of metal nanoparticles (NPs). [58] [59] [60] [61] Protein shells served as a template to restrain particle growth and as a coating to prevent coagulation/aggregation between NPs. Using various sizes of protein shells, various sizes of NPs can be easily synthesized for chemical, physical and bio-medical applications. [6] [62]

Experimental COVID-19 vaccines have been produced that display the spike protein's receptor binding domain on the surface of ferritin nanoparticles. [63]

Notes

The primary peptide sequence of human ferritin is: [64] 

MTTASTSQVR QNYHQDSEAA INRQINLELY ASYVYLSMSY YFDRDDVALK NFAKYFLHQS HEEREHAEKL MKLQNQRGGR IFLQDIKKPD CDDWESGLNA MECALHLEKN VNQSLLEFPS PISPSPSCWH HYTTNRPQPQ HHLLRPRRRK RPHSIPTPIL IFRSP.

See also

Related Research Articles

<span class="mw-page-title-main">Hereditary haemochromatosis</span> Medical condition

Hereditary haemochromatosis type 1 is a genetic disorder characterized by excessive intestinal absorption of dietary iron, resulting in a pathological increase in total body iron stores. Humans, like most animals, have no mechanism to regulate excess iron, simply losing a limited amount through various means like sweating or menstruating.

<span class="mw-page-title-main">Iron deficiency</span> State in which a body lacks enough iron to supply its needs

Iron deficiency, or sideropenia, is the state in which a body lacks enough iron to supply its needs. Iron is present in all cells in the human body and has several vital functions, such as carrying oxygen to the tissues from the lungs as a key component of the hemoglobin protein, acting as a transport medium for electrons within the cells in the form of cytochromes, and facilitating oxygen enzyme reactions in various tissues. Too little iron can interfere with these vital functions and lead to morbidity and death.

<span class="mw-page-title-main">Myelodysplastic syndrome</span> Diverse collection of blood-related cancers

A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include fatigue, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.

<span class="mw-page-title-main">Transferrin</span> Mammalian protein found in Homo sapiens

Transferrins are glycoproteins found in vertebrates which bind and consequently mediate the transport of iron (Fe) through blood plasma. They are produced in the liver and contain binding sites for two Fe3+ ions. Human transferrin is encoded by the TF gene and produced as a 76 kDa glycoprotein.

<span class="mw-page-title-main">Iron overload</span> Human disease

Iron overload is the abnormal and increased accumulation of total iron in the body, leading to organ damage. The primary mechanism of organ damage is oxidative stress, as elevated intracellular iron levels increase free radical formation via the Fenton reaction. Iron overload is often primary but may also be secondary to repeated blood transfusions. Iron deposition most commonly occurs in the liver, pancreas, skin, heart, and joints. People with iron overload classically present with the triad of liver cirrhosis, secondary diabetes mellitus, and bronze skin. However, due to earlier detection nowadays, symptoms are often limited to general chronic malaise, arthralgia, and hepatomegaly.

<span class="mw-page-title-main">Iron-deficiency anemia</span> Reduced ability of the blood to carry oxygen due to a lack of iron

Iron-deficiency anemia is anemia caused by a lack of iron. Anemia is defined as a decrease in the number of red blood cells or the amount of hemoglobin in the blood. When onset is slow, symptoms are often vague such as feeling tired, weak, short of breath, or having decreased ability to exercise. Anemia that comes on quickly often has more severe symptoms, including confusion, feeling like one is going to pass out or increased thirst. Anemia is typically significant before a person becomes noticeably pale. Children with iron deficiency anemia may have problems with growth and development. There may be additional symptoms depending on the underlying cause.

<span class="mw-page-title-main">Microcytic anemia</span> Medical condition

Microcytic anaemia is any of several types of anemia characterized by smaller than normal red blood cells. The normal mean corpuscular volume is approximately 80–100 fL. When the MCV is <80 fL, the red cells are described as microcytic and when >100 fL, macrocytic. The MCV is the average red blood cell size.

Anemia of chronic disease (ACD) or anemia of chronic inflammation is a form of anemia seen in chronic infection, chronic immune activation, and malignancy. These conditions all produce elevation of interleukin-6, which stimulates hepcidin production and release from the liver. Hepcidin production and release shuts down ferroportin, a protein that controls export of iron from the gut and from iron storing cells. As a consequence, circulating iron levels are reduced. Other mechanisms may also play a role, such as reduced erythropoiesis. It is also known as anemia of inflammation, or anemia of inflammatory response.

<span class="mw-page-title-main">Total iron-binding capacity</span> Medical blood test to measure transferrin

Total iron-binding capacity (TIBC) or sometimes transferrin iron-binding capacity is a medical laboratory test that measures the blood's capacity to bind iron with transferrin. Transferrin can bind two atoms of ferric iron (Fe3+) with high affinity. It means that transferrin has the capacity to transport approximately from 1.40 to 1.49 mg of iron per gram of transferrin present in the blood.

Transferrin saturation (TS), measured as a percentage, is a medical laboratory value. It is the value of serum iron divided by the total iron-binding capacity of the available transferrin, the main protein that binds iron in the blood, this value tells a clinician how much serum iron is bound. For instance, a value of 15% means that 15% of iron-binding sites of transferrin are being occupied by iron. The three results are usually reported together. A low transferrin saturation is a common indicator of iron deficiency anemia whereas a high transferrin saturation may indicate iron overload or hemochromatosis. Transferrin saturation is also called transferrin saturation index (TSI) or transferrin saturation percentage (TS%)

<span class="mw-page-title-main">Human iron metabolism</span> Iron metabolism in the body

Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease. Hematologists have been especially interested in systemic iron metabolism, because iron is essential for red blood cells, where most of the human body's iron is contained. Understanding iron metabolism is also important for understanding diseases of iron overload, such as hereditary hemochromatosis, and iron deficiency, such as iron-deficiency anemia.

<span class="mw-page-title-main">Hepcidin</span> Protein-coding gene in the species Homo sapiens

Hepcidin is a protein that in humans is encoded by the HAMP gene. Hepcidin is a key regulator of the entry of iron into the circulation in mammals.

<span class="mw-page-title-main">Ferroportin</span> Protein

Ferroportin-1, also known as solute carrier family 40 member 1 (SLC40A1) or iron-regulated transporter 1 (IREG1), is a protein that in humans is encoded by the SLC40A1 gene. Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of the cell. Ferroportin is the only known iron exporter.

<span class="mw-page-title-main">African iron overload</span> Iron overload disorder caused by consumption of home-brewed beer

African iron overload is an iron overload disorder first observed among people of African descent in Southern Africa and Central Africa. It is now recognized to actually be two disorders with different causes, possibly compounding each other:

<span class="mw-page-title-main">Beta thalassemia</span> Blood disorder

Beta thalassemias are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to clinically asymptomatic individuals. Global annual incidence is estimated at one in 100,000. Beta thalassemias occur due to malfunctions in the hemoglobin subunit beta or HBB. The severity of the disease depends on the nature of the mutation.

<span class="mw-page-title-main">Ferritin light chain</span> Protein found in humans

Ferritin light chain is a protein that in humans is encoded by the FTL gene. Ferritin is the major protein responsible for storing intracellular iron in prokaryotes and eukaryotes. It is a heteropolymer consisting of 24 subunits, heavy and light ferritin chains. This gene has multiple pseudogenes.

<span class="mw-page-title-main">Hemosiderosis</span> Iron metabolism disease

Hemosiderosis is a form of iron overload disorder resulting in the accumulation of hemosiderin.

Soluble transferrin receptor conventionally refers to the cleaved extracellular portion of transferrin receptor 1 that is released into serum. This receptor is a protein dimer of two identical subunits, linked together by two pairs of disulfide bonds. Its molecular mass 190,000 Dalton.

Hemochromatosis type 4 is a hereditary iron overload disorder that affects ferroportin, an iron transport protein needed to export iron from cells into circulation. Although the disease is rare, it is found throughout the world and affects people from various ethnic groups. While the majority of individuals with type 4 hemochromatosis have a relatively mild form of the disease, some affected individuals have a more severe form. As the disease progresses, iron may accumulate in the tissues of affected individuals over time, potentially resulting in organ damage.

Iron preparation is the formulation for iron supplements indicated in prophylaxis and treatment of iron-deficiency anemia. Examples of iron preparation include ferrous sulfate, ferrous gluconate, and ferrous fumarate. It can be administered orally, and by intravenous injection, or intramuscular injection.

References

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