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 ironresponsive 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.

Expression of the H-subunit and L-subunit of ferritin in bone marrow macrophages and cells of the erythron during cellular immune activation

“…In view of the presumed functional characteristics of the H-subunit of ferritin [37], the increase in its expression seen in this study is consistent with the role ascribed to ferritin in the sequestration and with-holding of iron. This accumulation of iron in the macrophages with consequential haemosiderosis of the macrophage and reduction in serum iron [21], will result in less iron reaching the cells of the erythron for the production of haemoglobin.…”

“…The second process, that could have brought about a lower observed increase in the H-subunit of ferritin, also induced by proinflammatory cytokines, is the degradation of ferritin during haemosiderin formation. As discussed elsewhere [37], H-subunit rich ferritins, in preference to L-subunit rich ferritins, are directed into lysosomes during the formation of haemosiderin. Of interest is the fact that activation of macrophages by pro-inflammatory cytokines such as TNF-α can result in the slower release of iron, thus supporting the proposed role of cytokines in ferritin-mediated iron sequestration by macrophages [38,39], and possibly an indirect role for H-subunits in the iron transfer block of inflammation.…”

Cell sensitivity to oxidative stress is influenced by ferritin autophagy

“…Finally and compellingly, for decades electron microscopists have described the presence of ferritin molecules inside the lysosomal compartment (for a review see ref. [7]). However, if most ferritin is heavily iron-loaded no further uptake will take place and its eventual degradation will further enhance lysosomal redox-active iron and sensitize the lysosomal compartment to oxidative stress.…”

“…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].…”

Enhanced iron and zinc accumulation in genetically engineered wheat plants using sickle alfalfa (Medicago falcataL.) ferritin gene

“…Ferritin is an intracellular plastid protein that controls iron sequestration, storage, and release (Koorts and Viljoen 2007). Thus, ferritin is an important gene for the regulation of iron accumulation in plants.…”