Ferritin
Overview
 
Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals. In humans, it acts as a buffer against iron deficiency and iron overload.

Ferritin is a globular protein
Globular protein
Globular proteins, or spheroproteins are one of the two main protein classes, comprising "globe"-like proteins that are more or less soluble in aqueous solutions...

 complex consisting of 24 protein subunits and is the primary intracellular iron-storage protein in both prokaryote
Prokaryote
The prokaryotes are a group of organisms that lack a cell nucleus , or any other membrane-bound organelles. The organisms that have a cell nucleus are called eukaryotes. Most prokaryotes are unicellular, but a few such as myxobacteria have multicellular stages in their life cycles...

s and eukaryote
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...

s, keeping iron in a soluble and non-toxic form.
Encyclopedia
Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals. In humans, it acts as a buffer against iron deficiency and iron overload.

Ferritin is a globular protein
Globular protein
Globular proteins, or spheroproteins are one of the two main protein classes, comprising "globe"-like proteins that are more or less soluble in aqueous solutions...

 complex consisting of 24 protein subunits and is the primary intracellular iron-storage protein in both prokaryote
Prokaryote
The prokaryotes are a group of organisms that lack a cell nucleus , or any other membrane-bound organelles. The organisms that have a cell nucleus are called eukaryotes. Most prokaryotes are unicellular, but a few such as myxobacteria have multicellular stages in their life cycles...

s and eukaryote
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...

s, keeping iron in a soluble and non-toxic form. Ferritin that is not combined with iron is called apoferritin.

Description

Ferritin is a protein of 450 kDa consisting of 24 subunits that is present in every cell type. In vertebrates, these subunits are both the light (L) and the heavy (H) type with an apparent molecular weight of 19 kDA or 21 kDA respectively; their sequences are about 50% homologous. Amphibians have an additional ("M") type of ferritin; the single ferritin of plants and bacteria most closely resembles the vertebrate H-type. Two types have been recovered in the gastropod Lymnaea, the somatic ferritin being distinct from the yolk ferritin (see below). An additional subunit resembling Lymnaea soma ferritin is associated with shell formation in the pearl oyster. Two types are present in the parasite Schistosoma
Schistosoma
A genus of trematodes, Schistosoma, commonly known as blood-flukes and bilharzia, includes flatworms which are responsible for a highly significant parasitic infection of humans by causing the disease schistosomiasis, and are considered by the World Health Organization as the second most...

, one in males, the other in females. All the aforementioned ferritins are almost similar, in terms of their primary sequence, with the vertebrate H-type. In E. coli, a 20% similarity to human H-ferritin is recovered. Inside the ferritin shell, iron ions form crystallite
Crystallite
Crystallites are small, often microscopic crystals that, held together through highly defective boundaries, constitute a polycrystalline solid. Metallurgists often refer to crystallites as grains.- Details :...

s together with phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...

 and hydroxide
Hydroxide
Hydroxide is a diatomic anion with chemical formula OH−. It consists of an oxygen and a hydrogen atom held together by a covalent bond, and carrying a negative electric charge. It is an important but usually minor constituent of water. It functions as a base, as a ligand, a nucleophile, and a...

 ions. The resulting particle is similar to the mineral ferrihydrite
Ferrihydrite
Ferrihydrite is a widespread hydrous ferric oxyhydroxide mineral at the Earth's surface, and a likely constituent in extraterrestrial materials. It forms in several types of environments, from freshwater to marine systems, aquifers to hydrothermal hot springs and scales, soils, and areas affected...

. Each ferritin complex can store about 4500 iron
Iron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...

 (Fe3+) ions.

Some ferritin complexes in vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...

s are hetero-oligomers of two highly-related gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

 products with slightly different physiological properties. The ratio of the two homologous protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s in the complex depends on the relative expression levels of the two genes.

Mitochondrial ferritin
Mitochondrial ferritin
Mitochondrial ferritin is a ferroxidase enzyme that in humans is encoded by the FTMT gene.It is classified as a metal-binding protein which is located within the mitochondria...

 was recently identified as a protein precursor, and is classified as a metal-binding protein that is located within the mitochondria. After the protein is taken up by the mitochondria it can be processed into a mature protein and assemble functional ferritin shells. Its structure was determined at 1.70 angstroms through the use of X-ray diffraction and contains 182 residues. It is 67% helical. The Ramachandran plot
Ramachandran plot
-Introduction and early history:A Ramachandran plot , originally developed in 1963 by G. N. Ramachandran C. Ramakrishnan and V...

  shows that the structure of mitochondrial ferritin is mainly alpha helical with a low prevalence of beta sheets. Unlike other human ferritin, it appears to have no introns in its genetic code.

Genetic structure

In human ferritin, intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...

s are present between the 34/5th, 82/3rd, and 14/5th amino acid residues; in addition, one to two hundred untranslated bases grace either end of the combined exons.
The Tyrosine residue at amino acid position 27 is thought to be associated with biomineralization.

Iron storage

Ferritin 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. The function and structure of the expressed ferritin protein varies in different cell types. This is controlled primarily by how much mRNA is translated, and how stable the mRNA is. mRNA concentration is further tweaked by changes to how it is stored and how efficiently it is transcribed. The presence of iron itself is a major trigger for the production of ferritin, with some exceptions (such as the yolk ferritin of the gastropod Lymnaea
Lymnaea
Lymnaea is a genus of small to large-sized air-breathing freshwater snails, aquatic pulmonate gastropod mollusks in the family Lymnaeidae, the pond snails.Lymnaea is the type genus of the family Lymnaeidae.-Species:...

, which lacks an iron-responsive unit).

Free iron is toxic to cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

 as it acts as a catalyst in the formation of free radicals from reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....

 via the Fenton Reaction. Hence vertebrates use an elaborate set of protective mechanisms to bind iron in various tissue
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...

 compartments. Within cells, iron is stored in a protein complex as ferritin or hemosiderin
Hemosiderin
thumb|Hemosiderin image of a kidney viewed under a microscope. The brown areas represent hemosiderinHemosiderin or haemosiderin is an iron-storage complex. It is always found within cells and appears to be a complex of ferritin, denatured ferritin and other material...

. Apoferritin binds to free ferrous iron and stores it in the ferric state. As ferritin accumulates within cells of the reticuloendothelial system
Reticuloendothelial system
"Reticuloendothelial system" is an older term for the mononuclear phagocyte system. The mononuclear phagocyte system consists primarily of monocytes and macrophages. The spleen is the largest unit of the mononuclear phagocyte system. The monocyte is formed in the bone marrow and transported by the...

, protein aggregates are formed as hemosiderin
Hemosiderin
thumb|Hemosiderin image of a kidney viewed under a microscope. The brown areas represent hemosiderinHemosiderin or haemosiderin is an iron-storage complex. It is always found within cells and appears to be a complex of ferritin, denatured ferritin and other material...

. Iron in ferritin or hemosiderin can be extracted for release by the RE cells although hemosiderin is less readily available. Under steady state
Steady state
A system in a steady state has numerous properties that are unchanging in time. This implies that for any property p of the system, the partial derivative with respect to time is zero:...

 conditions, the serum
Blood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...

 ferritin level correlates with total body iron stores; thus, the serum ferritin FR5Rl is the most convenient laboratory test to estimate iron stores.

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. It also plays a role in the haemolymph of the polyplacophora where it serves to rapidly transport iron to the mineralizing radula
Radula
The radula is an anatomical structure that is used by molluscs for feeding, sometimes compared rather inaccurately to a tongue. It is a minutely toothed, chitinous ribbon, which is typically used for scraping or cutting food before the food enters the esophagus...

.

Feroxidase activity

The heavy chain of Ferritin also possesses ferroxidase
Ferroxidase
Ferroxidase also known as Fe:oxygen oxidoreductase is an enzyme that catalyzes the oxidization of iron II to iron III:- Examples :Human genes encoding proteins with ferroxidase activity include:* CP – Ceruloplasmin* FTH1 – Ferritin heavy chain...

 activity, this involves the conversion of iron from the ferrous (Fe2+) to ferric (Fe 3+) forms. This limits the deleterious reaction which occurs between ferrous iron and hydrogen peroxide
Hydrogen peroxide
Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...

 known as the Fenton reaction which produces the highly damaging hydroxyl radical
Hydroxyl radical
The hydroxyl radical, •OH, is the neutral form of the hydroxide ion . Hydroxyl radicals are highly reactive and consequently short-lived; however, they form an important part of radical chemistry. Most notably hydroxyl radicals are produced from the decomposition of hydroperoxides or, in...

.

Immune response

Ferritin concentrations increase drastically in the presence of an infection or cancer; this is necessary to counter the infective agent's attempt to bind iron from the host's tissue. The inflammatory response may cause ferritin to migrate from the plasma to within cells, in order to deny iron to the infective agent.

Stress response

The concentration of ferritin has been shown to increase in response to stresses such as anoxia
Oxygen toxicity
Oxygen toxicity is a condition resulting from the harmful effects of breathing molecular oxygen at elevated partial pressures. It is also known as oxygen toxicity syndrome, oxygen intoxication, and oxygen poisoning...

; this implies that it is an acute phase
Acute phase
The Acute phase of an injury is the period of time in between when the injury is sustained, and the beginning of the sub-acute phase. Depending on the severity of injury, and the age and health of the patient, this phase can take up to four or five days...

 protein
Acute phase protein
Acute-phase proteins are a class of proteins whose plasma concentrations increase or decrease in response to inflammation...

.

Mitochondria

Mitochondrial ferritin
Mitochondrial ferritin
Mitochondrial ferritin is a ferroxidase enzyme that in humans is encoded by the FTMT gene.It is classified as a metal-binding protein which is located within the mitochondria...

 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.

Yolk

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

Industrial applications

Ferritin is also used in materials science as a precursor in making iron nanoparticle
Nanoparticle
In nanotechnology, a particle is defined as a small object that behaves as a whole unit in terms of its transport and properties. Particles are further classified according to size : in terms of diameter, coarse particles cover a range between 10,000 and 2,500 nanometers. Fine particles are sized...

s for carbon nanotube
Carbon nanotube
Carbon nanotubes are allotropes of carbon with a cylindrical nanostructure. Nanotubes have been constructed with length-to-diameter ratio of up to 132,000,000:1, significantly larger than for any other material...

 growth by chemical vapor deposition
Chemical vapor deposition
Chemical vapor deposition is a chemical process used to produce high-purity, high-performance solid materials. The process is often used in the semiconductor industry to produce thin films. In a typical CVD process, the wafer is exposed to one or more volatile precursors, which react and/or...

.

Expression

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

Diagnostic uses

Serum
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 ferritin levels are measured in medical laboratories
Medical laboratory
A medical laboratory or clinical laboratory is a laboratory where tests are done on clinical specimens in order to get information about the health of a patient as pertaining to the diagnosis, treatment, and prevention of disease.-Departments:...

 as part of the iron studies workup for anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...

 and for restless legs syndrome
Restless legs syndrome
Restless legs syndrome or Willis-Ekbom disease is a neurological disorder characterized by an irresistible urge to move one's body to stop uncomfortable or odd sensations. It most commonly affects the legs, but can affect the arms, torso, and even phantom limbs...

. 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
Anemia of chronic disease
Anemia of chronic disease, also referred to as anemia of inflammatory response is a form of anemia seen in chronic illness, e.g. from chronic infection, chronic immune activation, or malignancy...

 where ferritin is elevated in its capacity as an acute phase protein
Acute phase protein
Acute-phase proteins are a class of proteins whose plasma concentrations increase or decrease in response to inflammation...

 and not as a marker for iron overload.

A normal ferritin blood level, referred to as the reference interval is determined by many testing laboratories
Medical laboratory
A medical laboratory or clinical laboratory is a laboratory where tests are done on clinical specimens in order to get information about the health of a patient as pertaining to the diagnosis, treatment, and prevention of disease.-Departments:...

. The ranges for ferritin can vary between laboratories but are usually between 30–400 ng/mL (=μg/L) for males, and 15–200 ng/mL (=μg/L) for females.

Low

If the ferritin level is low, there is a risk for lack of iron, which could lead to anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...

. Low ferritin levels (<50 ng/mL) have, however, been associated with the symptoms of restless legs syndrome
Restless legs syndrome
Restless legs syndrome or Willis-Ekbom disease is a neurological disorder characterized by an irresistible urge to move one's body to stop uncomfortable or odd sensations. It most commonly affects the legs, but can affect the arms, torso, and even phantom limbs...

, even in the absence of anemia and sickness.

In the setting of anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...

, serum
Blood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...

 ferritin is the most specific lab test for iron deficiency anemia
Iron deficiency anemia
Iron-deficiency anemia is a common anemia that occurs when iron loss occurs, and/or the dietary intake or absorption of iron is insufficient...

. However it is less sensitive, since its levels are increased in the blood by infection, or any type of chronic inflammation, 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.

Low ferritin may also indicate hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...

, vitamin C
Vitamin C
Vitamin C or L-ascorbic acid or L-ascorbate is an essential nutrient for humans and certain other animal species. In living organisms ascorbate acts as an antioxidant by protecting the body against oxidative stress...

 deficiency or celiac disease.

Elevated

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 signalling body iron overload.

Ferritin is also used as a marker for iron overload disorder
Iron overload disorder
In medicine, iron overload indicates accumulation of iron in the body from any cause. The most important causes are hereditary hemochromatosis , a genetic disease, and transfusional iron overload, which can result from repeated blood transfusion....

s, such as hemochromatosis, hemosiderosis
Hemosiderosis
Idiopathic pulmonary haemosiderosis is a lung disease of unknown cause that is characterized by alveolar capillary bleeding and accumulation of haemosiderin in the lungs...

. Adult-onset Still's disease
Adult-onset Still's disease
Adult-onset Still's disease is a rare form of inflammatory arthritis that was characterized by EG Bywaters in 1971. The underlying cause is unknown. It usually presents with high spiking fevers, joint and muscle pains, a salmon colored rash and other symptoms of systemic inflammation.- History...

, porphyria
Porphyria
Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio-synthetic pathway . They are broadly classified as acute porphyrias and cutaneous porphyrias, based on the site of the overproduction and accumulation of the porphyrins...

 and Hemophagocytic lymphohistiocytosis
Hemophagocytic lymphohistiocytosis
Hemophagocytic lymphohistiocytosis , also known as hemophagocytic syndrome, is an uncommon hematologic disorder that, typically, clinically manifests as fever, hepatosplenomegaly, lymphadenopathy, jaundice and rash, with laboratory findings of lymphocytosis and histiocytosis, and the pathologic...

 are diseases 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
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...

. A normal C-reactive protein
C-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...

 can be used to exclude elevated ferritin caused by acute phase reactions.

Ferritin can be elevated during periods of acute malnourishment
Malnutrition
Malnutrition is the condition that results from taking an unbalanced diet in which certain nutrients are lacking, in excess , or in the wrong proportions....

.

Application

Cavities formed by ferritin and mini-ferritins (Dps
Dps (DNA-binding proteins from starved cells)
Dps proteins belong to the ferritin superfamily and are characterized by strong similarities but also distinctive differences with respect to “canonical” ferritins....

) proteins have been successfully used as the reaction chamber for the fabrication of metal nanoparticles (NPs). Protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 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

See also

  • Bacterioferritin
    Bacterioferritin
    Bacterioferritin is an oligomeric protein containing both a binuclear iron centre and haem b. The tertiary and quaternary structure of BFR is very similar to that of ferritin. The physiological functions of BFR, which may be other than just iron uptake, are not clear. BFR forms a roughly...

  • Dps (DNA-binding proteins from starved cells)
    Dps (DNA-binding proteins from starved cells)
    Dps proteins belong to the ferritin superfamily and are characterized by strong similarities but also distinctive differences with respect to “canonical” ferritins....

  • Transferrin
    Transferrin
    Transferrins are iron-binding blood plasma glycoproteins that control the level of free iron in biological fluids. In humans, it is encoded by the TF gene.Transferrin is a glycoprotein that binds iron very tightly but reversibly...

  • Ferritin light chain
    Ferritin light chain
    Ferritin light chain is a protein that in humans is encoded by the FTL gene.It is abnormally expressed in fetuses of both IVF and ICSI, which may contribute to the increase risk of birth defects in these ART....

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