Iron Homeostasis

• Chronic disease (NCI)


  A disease or condition which lasts 3 or more months
• Chronic diseases tend to get worse with age and in most cases they can be treated but not cured
• Most common chronic diseases

  • Cancer
  • Heart disease
  • Stroke
  • Diabetes
  • Arthritis
• Haidar 2023


  Increased exposure to environmental metals = chronic disorders
• Valasatava 2018


  Metals play an important role in biological systems as both catalytic and structural cofactors and ~50% of proteins contain metals
• Cells have mechanisms to control the level of metals required in the body and to ensure the correct metal reaches the appropriate protein
• Importance of iron

  • ~70% of iron in the body is incorporated into haemoglobin in red blood cells
  • Iron is involved in Fe-S clusters
  • In the nucleus, DNA repair helicases contain catalytic iron centres
• Metal homeostasis


  Occurs to meet metal specific requirements to ensure proteins function as required but that metal toxicity is prevented
• Mechanisms of metal homeostasis

  1. Transcription factors sense levels of metals within the cell and transcribe metal importers if required to bring more metal into the cell

  2. Chaperones within the cell distribute metals to the correct location

  3. Metals are stored, and stopped from entering cells to prevent metal toxicity
• Iron Uptake


  • Iron is obtained from the diet, either through foods or supplementation
  • Supplements are usually iron sulphate or iron chloride
  • Iron in the diet is mostly obtained from red meat consumption (high haem content) in the form of Fe2+
  • Pulses also contain iron as pulses take in iron from the soil in the form of Fe3+
  • The different iron oxidation states are important to note as this determines which uptake route it will follow
  • The dietary source dictates the oxidation state of iron, in turn affecting the absorption method
  • Iron can only be absorbed as Fe2+
• Iron Excretion

  • Contrasting to other metals such as copper, there is no excretion mechanism for iron and excess iron is instead stored in the liver
  • Some iron (1-2mg/day) is lost due to the physical loss of cells e.g. Skin shedding, hair follicle loss etc
  • Uptake of iron is therefore more tightly regulated by enterocytes in the gut
• Ogun 2022 General Iron Uptake Mechanism


  1. Dietary iron is absorbed into plasma and bound to an iron transferrin complex (shuttles iron through the blood to various tissues)

  2. The iron transferrin shuttles iron through the circulatory system and iron is incorporated in RBCs

  3. The RBCs eventually degrade and iron is released into plasma

  4. Either more RBCs form or if iron is in excess it is shuttle to the liver until more iron is required
• Due to the lack of excretion, iron uptake is tightly regulated so iron homeostasis can occur
• Fe3+ Uptake (e.g. Pulses)


  1. Fe3+ is reduced to Fe2+ by Dcytb so it can be absorbed

  2. Fe2+ enters the enterocyte (gut lumen cells) through DMT1 (iron transporter)

  3. Fe2+ can either be stored by binding to ferritin or can be exported into serum by ferroportin

  4. Once in serum, iron is transported by transferrin. However, transferrin carries Fe3+ only so the Fe2+ must be oxidised by Hephaestin
• Fe2+ Uptake (e.g. Red meat or recycled RBCs)


  1. Fe2+ is transported into the cell by the HCP1 transporter

  2. This binds to HO1 to leave free Fe2+ in solution which can then either be used for storage by binding to ferritin or it can bind to ferroportin for transport into serum, bind to hephaestin to be oxidised to Fe3+, then bind to transferrin to be transported around the body
• Iron Delivery

  1. Iron is transported in serum by binding to transferrin

  2. This iron bound transferrin is endocytosed into cells by TFR1 (Transferrin receptor)

  3. The pH drop within the endosome causes transferrin to release the Fe3+ bound

  4. Steap3 reduces Fe3+ to Fe2+

  5. DMT1 transports Fe2+ into the cell
• Iron Recycling from RBCs

  1. Senescent (old) RBCs engulfed by macrophage

  2. Fe2+ is striped out of haem by a series of processes including HO1

  3. Ferroportin transports Fe2+ to serum

  4. Ceruloplasmin oxidises Fe2+ to Fe3+ so it can bind to transferrin
• Iron Sensing Mechanisms


  1. Regulating iron transporter expression

  2. mRNA transcript levels regulated

  3. Iron release regulation
• Iron Transporter Regulation


  1. HIF-2a senses iron conditions

  2. When iron is low, HIF-2a activates Dcytb and DMT1 transcription so more iron can be transported into the cell

  3. When iron is high, PHD enzymes bind to HIF-2a and block it translocating to the nucleus and also degrade it. Therefore, iron transporter transcription is switched off
• mRNA Regulation


  1. In low iron conditions, iron reporter proteins (IRPs) bind to genes which will transcribe iron removal proteins e.g. Ferritin for storage and ferroportin for transport

  2. IRP also binds to DMT1 and stabilises it so more iron can be transported in

  3. In high iron conditions, Fe-S clusters form and bind to IRPs so IRPs don't bind to mRNA and iron is stored and not transported into the cell etc
• Iron Release Regulation


  1. Hepcidin binds to ferroportin and blocks the release of iron from the cells

  2. High hepcidin levels = low circulatory iron (high dietary iron levels are stored)

  3. HFE modulates the expression of hepcidin (turns it off when iron is needed) via the Bmp/SMAD signalling pathway
• In high iron conditions ferroportin is high, and transferrin is high so high levels of iron are transported to serum. Hepcidin levels are increased via HFE and the Bmp/SMAD signalling pathway. Increased hepcidin binds to FPN blocking the release of iron into serum preventing high iron serum
• In low iron conditions FPN is low, TF is low, hepcidin production is switched off via HFE and Bmp/SMAD signalling, therefore FPN is not degraded
• However in low conditions, only what is taken in through the diet can be imported. Even though FPN is available, iron may not be available to be transported - anaemia
• WHO 2023 Anaemia


  • Occurs when iron levels are deficient
  • Major public health concern particularly affecting young children and women
  • Can cause developmental delays and has been associated with poor maternal/birth outcomes incl. Premature birth, low birth weight, maternal mortality
  • Best treatment = iron supplementation
• Adams 2015 Haemochromatosis


  • Affects 1 in 300-500 individuals
  • Tissue damage caused by iron overload due to low hepcidin levels and mutations in iron uptake proteins e.g. HFE, FPN, TFR2
• Symptoms of Haemochromatosis


  • Cirrhosis
  • Diabetes
  • Skin pigmentation
  • Lethargy, weakness, and sleep disturbance
  • Cardiac damage
• Diagnosis of Haemochromatosis

  • Ferritin levels high (>200ng/ml in women and >300ng/ml in men)
  • MRI of liver (iron is magnetic so very accurate measurement)
  • Liver biopsy
  • Genotyping
• Treatment of Haemochromatosis

  • Regular phlebotomy (lowers iron stores)
  • Iron chelators e.g. Deferoxamine
  • Liver transplant in severe cirrhosis cases
• Ems 2023


  Iron can only be absorbed as Fe2+