Iron transport and homeostasis 2

• Describe the structure of transferrin

  Consists of two homologous Domains, with each containing one high affinity pH depending Fe (III) binding site. Transferrin Is usually found in its monomeric form But its affinity for iron increases with pH.
• Describe the transferrin receptor

  The transferrin receptor acts as the gatekeeper of iron acquisition in most cell types. It consists of a disulphide linked transmembrane glycoprotein homodimer, with a cytoplasmic domain essential for receptor internalisation (tetrapeptide sequence acts as a signal sequence for high-efficiency endocytosis. The affinity of the transferrin receptor for transferrin varies depending on the concentration of transferrin and its iron status, with the highest affinity for the differic transferrin.
• Describe transferrin receptor endocytosis

  1. Transferrin binds to receptor and it internalised within a clathrin coated pit.
  2. Forms an endosome which merges with proton pumps that pump protons into the endosome
  3. This lowers pH and therefore lowers the affinity of transferrin for iron, leading to dissociation of iron.
  4. DMT1 (covalent metal transporter) then fuses with the endosome and transports iron out of the endosome to a labile intracellular ‘transit’ pool of Fe (II)
• Describe ferritin

  Ferritin is a protein that sequesters and stores iron as a solid phase material. It is made up of 24 symmetrically related subunits split into light and dark subunits. Inside ferritin, iron is stored in the ferric state as a ferric oxyhydroxide, via the action of the H-subunit, which acts as a ferroxidase by promoting oxidation of Fe)II) to Fe (III). Ferritin synthesis is inducible by iron or oxidative stress and inflammatory cytokines.
• Describe the mechanism of control for ferritin and transferrin expression

  In low iron- iron response proteins (IRPs) bind to the 5’ iron response elements (IREs) on mRNA and lead to inactivation of ferritin translation, whilst also binding to 3’ IREs on transferrin mRNA and stabilising it.

  In high iron- iron binds to IRPs, which prevents them from binding to 5’ IRE on ferritin mRNA and leads to translation activation. However, IRPs cannot bind to 3’ IREs on transferrin, leading to inhibition of translation.
• What are iron response proteins?

  IRP1- shares homology with mitochondrial aconitase, which is a 4Fe-S cluster contains enzyme of the citric acid cycle. Depletion in iron leads to lack of 4Fe-S clusters and IRP-1 loses its aconitase activity; instead, binding to IREs with high affinity.

  IRP2- less known about but thought to be an iron sensor.
• What is the action of hepcidin in iron homeostasis?

  Hepcidin is a protein that is found to be predominantly expressed in the liver and is a repressor of iron absorption by repressing the activity of ferroportin, which is responsible for transporting iron across the basolateral membrane in the intestines. Expression of Hepcidin is decreased when the body’s demands for iron are high.
• What is hypochromic microcytic anaemia?

  This is the most common form of anaemia and is the result of nutritional iron deficiency, which is commonly due to bleeding disorders or seen in children. It is defined by a reduced corpuscular volume of RBCs= 80-100 femtolitres. The result of this decreased volume is a reduction in Hb.
• Describe the role of HIF-2Alpha in response to low iron

  A reduction in oxygen uptake by the alveolae leads to arterial hypoxaemia, which is detected by prolyl hydroxylases (PDHs) found within peritubular fibroblasts. The reduced iron level suppresses the activity of PDHs and leads to stabilisation of the alpha subunit of HIF-2Alpha. This leads to increased transcription of erythropoietin. HIF-2Alpha also contains IREs in its 5’ untranslated region, which, under iron deficient conditions, binds to IRP1 to inhibit HIF-2Alpha translation.
• Describe the action of Epo in response to iron levels

  Epo stimulates erythropoiesis, which is an high iron-consuming process, therefore it must be controlled in times of iron-deficiency. Epo-controlled erythroferrone and growth differentiation factor 15 are produced by erythroid precursor cells and act to reduce the expression of hepcidin. This results in elevated iron release from storange organs including macrophages and enhanced absorption of dietary iron by enterocytes.
• Describe the epithelial response to low iron

  Increased levels of HIF-alpha is leads to expression of DMT1, duodenal cytochrome B and ferroportin 1 In the epithelial duodenum and inhibit Hepcidin production.
• Describe the different types of iron overload

  1. Hereditary haemochromatosis: caused by mutations involved in absorption of iron, leading to gradual build up of iron in the body.
  2. Secondary iron overload: result of:
  3. severe chronic haemolysis
  4. multiple frequent blood transfusions
  5. excess parenteral iron supplements
  6. excess dietary ion
• Describe the different types of haemochromatosis

  Type 1: classical, mutations in human homeostatic iron regulatory protein known as HFE protein.

  Type 2: juvenile, mutations in haemojuvelin

  Type 2B: juvenile, mutations in hepcidin

  Type 3: mutations in transferrin receptor 3

  Type 4: mutations in ferroportin
• Describe renal hepcidin antimicrobial peptide

  1. Increasing iron ingestion leads to increases serum iron availability
  2. Stimulates increase in HAMP production, which is released by the liver.
  3. HAMP inhibits iron reabsorption by blocking ferroportin in renal tubules.
  4. Inhibition of iron absorption leads to renal iron retention while deceasing systemic iron availability and consequently reducing liver iron overload.
• Describe how HAMP mutations lead to iron overload

  Mutations in HAMP decrease its responsiveness in the renal tubules and leads to unregulated iron absorption. This, in turn, prevents renal ion retention while increasing systemic iron availability and subsequently increasing liver iron overload.
• Describe the treatments for iron overload

  • low iron diet
  • Iron chelation therapy
  • e.g., deferoxamine
  • Phlebotomy: take a small amount of blood every month