Iron metabolism

Outline human iron requirements

See earlier post: Iron

Describe the function of transport & storage proteins in iron metabolism

The main transport proteins are transferrin and mobilferrin. Transferrin, which is found in plasma, transports iron around the body. Mobilferrin transports iron within cells. The main storage protein is ferritin, which sequesters iron inside cells. (There is some ferritin in plasma, but very little.) Iron must be Fe³⁺ (not Fe²⁺) to be stored. Ferroxidase converts Fe²⁺ to Fe³⁺, and ferroductase converts Fe³⁺ to Fe²⁺. At high concentrations of iron, ferritin combines and forms haemosiderin, which is very toxic and leads to cell death.

Transport and storage proteins, as well as formation of haemosiderin, are all important ways of reducing the proportion of bound iron. Why is this important? Well, iron is involved in the production of reactive oxygen species. As mentioned here, the Fenton reaction causes production of hydroxyl radicals:

Fe²⁺ + H₂O₂ --> Fe³⁺ + OH^- + OH*

Fe³⁺ can take part in a similar reaction that produces hyperoxyl radicals (OOH*):

Fe³⁺ + H₂O₂ --> Fe²⁺ + H⁺ + OOH*

OH* and OOH* can cause a lot of damage, due to their high reactivity with lipids, DNA and protein.

Describe the mechanisms of iron uptake, storage & transport throughout the body

Uptake

There are two main types of iron: haem iron (iron bound to haem) and non-haem iron. Haem iron is more readily absorbed than non-haem iron, but overall iron absorption is fairly poor. Iron absorption can be increased or decreased by the presence of various dietary complexes. Complexes that increase absorption include ascorbate, glutathione, lactate, pyruvate, cysteine and histidine. Complexes that decrease iron absorption include phytates, tannates, oxalates, carbonates and other minerals (e.g. magnesium and zinc).

First, let's look at how non-haem iron is absorbed! Non-haem iron can exist in either Fe²⁺ or Fe³⁺ states. Since only Fe²⁺ can be absorbed, Fe³⁺ must first be converted into Fe²⁺ by the enzyme Dcytb, which is located on the apical surface of enterocytes. Fe²⁺ is then co-transported with H⁺ (thus requiring a proton gradient) via the DCT1 (divalent cation transporter) symporter. Once inside the cell, Fe²⁺ is bound to mobilferrin and transported to the basolateral membrane, where IREG1 (a.k.a. ferroportin, or FP1) transports iron into the interstitial space. At the same time that iron is being transported, the enzyme hephastin, which is also on the basolateral side, oxidises Fe²⁺ to Fe³⁺, allowing it to bind to transferrin for transport around the blood.

Haem iron absorption is a lot simpler. Haem iron is taken up by the haem carrier protein 1 (HCP1). Once inside the cell, haem oxygenase liberates Fe²⁺, which then binds to mobilferrin. The rest of the process takes place the same way as for non-haem iron.

Storage

As mentioned earlier, iron can be bound to and stored in ferritin. If iron stores are too high, ferritin can combine to form haemosiderin deposits, causing cell death. The dead cells are then sloughed off, removing that iron for good.

Transport

Iron is transported around the plasma by binding to transferrin. Target cells take it up via receptor-mediated endocytosis with transferrin receptors. Once inside the cell, iron is released from transferrin via DMT1. It can then be incorporated into haem or bound to ferritin for storage.

Describe the regulation of plasma [Fe]

Every day, we use around 20mg to make red blood cells. When those blood cells reach the end of their lifespan, macrophages of the reticuloendothelial system gobble them up, releasing the iron (around 20mg/day is regenerated in this method). We also take in and excrete around 1-2mg/day, but excretion is greater in females (particularly during menstruation). Excretion is also poorly controlled, so most iron regulation is done via regulating intake.

The important hormone to know here is hepcidin, which is secreted by the liver. Hepcidin can bind to IREG1/ferroportin, causing it to be sequestered and degraded. As IREG1/ferroportin is the only cellular iron exporter in vertebrates, and is found in quite a lot of cells (aside from enterocytes, it's also found in macrophages, hepatocytes, spleen and placenta), hepcidin can have a substantial efffect on plasma iron concentrations.

Describe iron related pathologies

I've spoken a little bit about anaemia (too little iron) and haemochromatosis (too much iron) here, but now I'm going to go into even more detail on haemochromatosis! Most genetic haemochromatosis is caused by a C282Y mutation in the HFE gene, which codes for a dominant regulator of hepcidin production. When HFE is mutated, hepcidin isn't produced, so iron uptake is greatly increased. Other genes that might cause haemochromatosis if mutated are HAMP (hepcidin), HJV (haemojuvelin) and TfR2 (transferrin receptor type 2).