Ferritin and ferritin isoforms I: Structure–function relationships, synthesis, degradation and secretion

Abstract

Ferritin is the intracellular protein responsible for the sequestration, storage and release of iron. Ferritin can accumulate up to 4500 iron atoms as a ferrihydrite mineral in a protein shell and releases these iron atoms when there is an increase in the cell's need for bioavailable iron. The ferritin protein shell consists of 24 protein subunits of two types, the H-subunit and the L-subunit. These ferritin subunits perform different functions in the mineralization process of iron. The ferritin protein shell can exist as various combinations of these two subunit types, giving rise to heteropolymers or isoferritins. Isoferritins are functionally distinct and characteristic populations of isoferritins are found depending on the type of cell, the proliferation status of the cell and the presence of disease. The synthesis of ferritin is regulated both transcriptionally and translationally. Translation of ferritin subunit mRNA is increased or decreased, depending on the labile iron pool and is controlled by an iron-responsive element present in the 5′-untranslated region of the ferritin subunit mRNA. The transcription of the genes for the ferritin subunits is controlled by hormones and cytokines, which can result in a change in the pool of translatable mRNA. The levels of intracellular ferritin are determined by the balance between synthesis and degradation. Degradation of ferritin in the cytosol results in complete release of iron, while degradation in secondary lysosomes results in the formation of haemosiderin and protection against iron toxicity. The majority of ferritin is found in the cytosol. However, ferritin with slightly different properties can also be found in organelles such as nuclei and mitochondria. Most of the ferritin produced intracellularly is harnessed for the regulation of iron bioavailability; however, some of the ferritin is secreted and internalized by other cells. In addition to the regulation of iron bioavailability ferritin may contribute to the control of myelopoiesis and immunological responses.

Key words:  :

• Ferritin
• haemosiderin
• H-subunit
• L-subunit
• isoferritins

Notes

Synthesis of ferritin: Transcription (I) of the H-subunit and L-subunit ferritin genes occurs in the nucleus of the cell. This is followed by (II) the translocation of the H-subunit and L-subunit mRNA to a pool of translatable ferritin mRNA. Translation of the H-subunit and L-subunit mRNA of ferritin from this pool of translatable ferritin mRNA is largely controlled by iron from the labile iron pool (III) that contains the metabolically and catalytically reactive iron. In this pool of translatable ferritin mRNA (II) translation of the H-subunit and L-subunit mRNA, respectively, is prevented by binding of the iron-responsive protein (IRP) to the iron-responsive element (IRE) on the 5′ non-coding stretch of H-subunit and L-subunit mRNA (II.1). Displacement of the IRP takes place upon binding of iron to IRP followed by translation (II.2). Translation of the ferritin mRNA takes place on free polyribosomes in the cytosol (IV). This is followed by folding of the translated H-subunit and L-subunit polypeptides into the α-helix rich tertiary structures of the H-subunit and L-subunit. These subunits form a pool consisting of H-subunits and L-subunits (V). From this pool of H-subunits and L-subunits the protein shell of ferritin consisting of 24 subunits symmetrically arranged is assembled (VI). The completely assembled iron-free ferritin (apoferritin) forms a pool of apoferritin containing different combinations of H- and L-subunits (VII). Ferritin can also be secreted from the cell (VIII).

Sequestration of iron (IX): Sequestration of iron is shown to occur after the ferritin protein shell is fully assembled. (IX.1) Oxidation of Fe²⁺ is performed by the ferroxidase centre of the H-subunit. This is followed by nuclei formation and iron core growth facilitated by L-subunits. Once the iron core reaches a sufficient size oxidation of Fe²⁺ can take place on the surface of the iron core. (IX.2) Oxidation of Fe²⁺ is performed by the ferroxidase centre of the H-subunit. However, if ferritin contains insufficient quantities of L-subunit for nuclei formation the formed Fe³⁺ can leave the ferritin molecule and move to a ferritin molecule containing sufficient quantities of L-subunit or an already developed iron core, or (IX.3) the formed Fe³⁺ can leave the ferritin molecule followed by hydrolysis of the Fe³⁺ on the outer surface of the ferritin molecule and ferritin aggregation.

Release of iron from ferritin (X): The release of iron from ferritin is shown to occur either by (X.1) Simultaneous entry of a reductant and a chelator to the interior of the ferritin protein shell whereupon Fe³⁺ is reduced to Fe²⁺ in the confinements of the ferritin protein shell by the reductant followed by the release of Fe²⁺ as a Fe²⁺-chelator complex, or (X.2) entry of only a chelator to the interior of the ferritin protein shell in which case Fe³⁺ is not reduced and leaves as a Fe³⁺-chelator complex.

Distribution of ferritin (XI): Ferritin occurs in the cytosol either as dispersed ferritin particles (XI.1) or as ferritin clusters (XI.2).

Degradation of ferritin (XII): Two different processes can result in the degradation of ferritin. (XII.1) Degradation by the 20s proteasome enzymatic system, which recognizes and degrades oxidized ferritin. (XII.2) Degradation by lysosome enzymes in a secondary lysosome. Ferritin finds its way into the secondary lysosome by either autophagocytosis (XII.2.1) or by targeting of ferritin to the secondary lysosome (XII.2.2). The latter can lead to haemosiderin and eventually siderosome formation.

Nuclear ferritin (XIII): Ferritin is also found in the nucleus. The ferritin in the nucleus consists of cytosolic H-subunit rich ferritins that are translocated back to the nucleus from the pool of apoferritin (VII) where these ferritins can form stable complexes with the DNA.

Mitochondrial ferritin (XV): Mitochondrial ferritin contains 24 identical subunits transcribed from a different gene than that for the cytosolic H-subunit and L-subunit (XIV). Upon transcription and translation the mitochondrial ferritin subunit polypeptide is translocated into the matrix of the mitochondria (XV.1). This is followed by the cleavage of the signal sequence and folding of the mitochondrial ferritin subunit (XV.2). Typical hollow spherical ferritin shells containing 24 subunits are then assembled from these subunits (XV.3). Cytosolic iron from the labile iron pool (III) transverses the double membrane of the mitochondria followed by sequestration by mitochondrial ferritin (XV.4).

Processes involved in cellular iron acquisition (XVI–XVIII): (XVI) The transferrin receptor binds transferrin and is endocytosed. Upon acidification of the endosome iron is released into the labile iron pool (III). (XVII) The ferritin receptor binds ferritin and is endocytosed. Ferritin is degraded in a secondary lysosome and the released iron joins the labile iron pool (III). (XVIII) Red blood cells are phagocytosed followed by degradation and the release of heme iron by heme oxygenase. The released iron joins the labile iron pool (III).