Homeostasis of Iron

• How does the redox of iron make it special compared to other elements in the body?

  The redox potential is [Fe^3+/2+], modulated by the ligand it binds to

  Means that iron is suited to catalysing a diverse range of biochemical reactions across a wide pH range
• Give overview of uses for iron in body

  DNA replication and repair, cellular respiration, oxygen sensing, collagen synthesis, myelin biosynthesis, neurotransmitter release, oxygen storage and transport, vitD metabolism

  Iron either found as Fe, heme-Fe, or Fe-S clusters for these
• What are the effects of excess iron?

  Causes generation of reactive oxygen species, which cause oxidative damage to lipids, proteins, and DNA, leading to cell ageing, inflammation, and cell death
• What are the different pools of iron in the body?

  4 different pools - Largest is iron storage in the liver and short term storage in the gut, second is reticular endothelial system (RBCs, spleen, bone marrow), third is non-erythroid organs, and fourth is circulating iron (normally bound to transferrin chaperone, but some NTBI)
• Where is iron acquired from in the body?

  ~1.5mg from the gut daily, mobilisation of iron stores when needed, 25mg daily from recycling of RBCs (use heme oxygenases in the spleen, though same amount then goes into making more RBCs - self-sustaining)
• How is iron lost?

  We don't have an active mechanism to lose iron, so not much iron lost

  ~1.5mg/day lost form sluffing in gut, ~50mg lost per menstruation cycle, and ~500mg lost during pregnancy, with a bit more lost during labour
• How is iron export into the blood regulated?

  Transported by the ferroportin iron transporter from the inside to the outside of cells in the spleen, GI tract, and liver

  Hepcidin produced by the liver to regulate this process - binds to ferroportin to cause it to be internalised (produced when high transferrin saturation sensed, to reduce it - reduce iron in the circulation), production inhibited when low transferrin saturation - Hepcidin production subject to tight homeostatic control
• How is production of hepcidin controlled?

  The hepcidin gene promoter region has BREs - allow the gene to respond to BMP2 and BMP6 downstream signalling (though accessory proteins required as well)

  Low transferrin saturation means accessory protein HFE preferentially binds TfR1, sequestered here so it cannot join the complex, hepcidin not expressed

  In high Tf saturation, HFE is pushed away, binds to the TfR, translocate to the receptor complex to activate it, SMADs phosphorylated, bind to BREs in the hepcidin gene to activate it, reduces iron in the circulation (blocks ferroportin)
• Describe causes of iron homeostasis disorders

  Generally mutations in the hepcidin BRE complex - failure to sense Tf saturation

  Haemochromatosis 1 - HFE mutations, don't bind complex, don't bind to BREs to activate the hepcidin gene, constant high iron levels in circulation

  Haemochromatosis 2a - Mutations hemojuvelin (accessory protein), so low hepcidin produced

  Haemochromatosis 2b - mutations in hepcidin gene itself so not functional or not expressed enough

  Haemochromatosis 3 - Mutations TfR2

  High Tf saturation, so high NTBI forms ROS that damage tissues - transport not regulated by iron
• General effects of hereditary hemochromatosis

  Buid up of ROS in liver - cause hepatomegaly, cirrhosis, and hepatocellular carcinoma

  Highly expressed L and T type calcium channels in the heart take up iron in a way not sensitive to cellular iron levels, cause cardiac arrhythmia and cardiac failure

  Some transporters on beta cells, so can lead to diabetes mellitus

  Also causes chronic fatigue, hypopituitarism, melanoderma, skin dryness, white nails, koilonychia, joint pain, and osteoporosis

  Conditions more prevalent in men, may be due to some protection from menstruation in women
• What are two treatments for hemochromatosis?

  Phlebotomy (take blood to reduce iron), and chelation (chelator given that enters cells and takes up iron, released in the urine)

  Both of these have sig side effects though
• Causes and symptoms of iron deficiency

  Functional iron deficiency due to inflammation through raised hepcidin, absolute deficiency due to low dietary content, excessive demand (pregnancy), or excessive loss (menstruation etc)

  Iron supply first lost to liver, spleen, and gut, and after this runs out then erythroid ion begins to be depleted, iron-deficient anaemia manifests - many organs affected before iron deficiency begins to be treated
• Draw diagram describing iron fluxes in the cell

  Opposite for excess cellular iron

  Not all cells have ferroportin, only in tissues of iron supply (gut, liver, spleen), and some cardiovascular cell types

  
• How do cells know how much labile iron is in them?

  IRP1/2- when plenty of iron, IRP1 behaves as aconitase - has an Fe-S cluster in it, behaves like enzyme in the TCA cycle, IRP2 degraded via FBXL5 complex (activation requires iron)

  When iron deficiency, cannot make Fe-S clusters so IRP2 stabilised, IRP1 turns into iron binding protein, regulate transcription in iron homeostasis

  Opposite function based on iron availability

  IRP1/2 can bind to 5'UTRs to inhibit iron response element translation and increase iron storage +usage + export, bind to 3' UTRs to stabilise transcript for iron uptake
• Effects of failure to sense cellular iron

  Loss of IRPs means iron sequestration in ferritin

  Progressive neurodegeneration - cannot acquire enough iron for myelination
• Describe the cross-talk in erythropoiesis

  Cross talk renal interstitial fibroblasts (IFs) cellular Fe sensing and hepatocyte systemic Fe sensing- tether RBC production to Fe

  Anaemia- kidney IFs sense reduced O2 capacity blood, HIF2 upregulated, EPO to bone marrow -> more RBCs, depletes blood Fe

  Bone marrow stops liver hepcidin (HEP) production, so more Fe for RBCs- kidneys sense Fe depletion, IFs stop making EPO, fewer RBCs made to allow Fe recovery

  Liver senses Tf saturation, low liver Fe suppresses HEP production

  EPO stimulation bone marrow produces erythroferrone- reduce HEP production