Iron

Question 1

What is iron used for in the body?

Answer 1

75% associated haemoglobin (RBC)
25% for enzymes (Pirin - Transcription cofactor, DNA primase, DNA repair helicase (ion-sulphur complex)
Rest stored in ferritin

Question 2

What is ferritin?

Answer 2

Iron storage molecule - can store up to 4,000 atoms of Iron - contains iron oxidase enzyme which converts Fe2+ to Fe3+ to stop Fenton reaction

Question 3

What is the recommend daily intake of Iron?

Answer 3

Adults - 8mg/day

pregnant women - 27 mg/day

Question 4

What are the main sources of iron in the diet?

Answer 4

Haem iron - Fe2+ (Meat)

Non-haem iron - Fe3+ (Vegetables, bean, pulses)

Question 5

How do we get iron into our body?

Answer 5

Enterocytes
Haem iron can enter directly using HCP1 transporter
Non-haem iron is converted to Fe2+ using DCYTB (iron reductase) and then enters using DMT1 transporter
Iron can either be stored in ferritin or is transported into the blood using FPN
Once in blood, Fe2+ converted to Fe3+ using Hephaestin and it can bind to Transferrin (differic)

Question 6

How do we get iron into our cells?

Answer 6

Differic transferrin binds to TFR1 - causes receptor mediated endocytosis - ph Low in vesicle (7.4-6.2) and causes dissciation of iron from transferrin.
Fe3+ converted to Fe2+ using Steap3 (reductase)
Fe2+ moves out of endosome via DMT1
Transferrin recycled to surface

Question 7

How is iron recycled from RBCs?

Answer 7

Macrophages
Haem oxygenase breaks down haem in RBC - releases iron - transported out via FPN
Ceruloplasmin converts Fe2+ to Fe3+ and allows binding to Transferrin

Question 8

What are the two arms of iron sensing in the body?

Answer 8

Cellular

System

Question 9

How does cellular sensing work?

Answer 9

IRPs - aconitase like proteins bind IREs on mRNA 5’ or 3’ ends and regulate transcription (either repress or stabilise) In low Iron, IRP binds IRE on 5’ UTR of ferritin - causes repression - reduced iron storage. In low iron, IRP binds IRE on transferrin mRNA to increase transport of iron. Overall when we detect low iron cytolic levels - we want to increase circulation of iron.

HIF2 - Transcription factor - in low iron levels, HIF increased DMT1 and DCTYB transcription to increase iron uptake into cells. In high iron levels, HIF is sequestered and degraded due to PHD1/2/3 enzymes being activated and adding OH group to the HIF2.

Question 10

How does systemic sensing work?

Answer 10

Hepcidin - 25AA - produced in liver - negative regulator of iron - regulated by sensing circulation iron levels (differic transferrin) and hepatocyte level (ferritin)

Circulation sensing - HFE - in high iron, HFE binds TFR2 and leads to ERK phosphorylation leading to increased hepcidin production. In low iron, HFE binds to TFR1 (since there is not enough differic transferrin to displace it) and as a result ERK is not phosphorylated so hepcidin is NOT increased

Hepatocyte ferritin sensing - In high levels, BMP6 binds to HJV and BMPR which leads to SMAD activation and increases Hepcidin. In low levels, proteinases removes HJV and mops up BMP6 to reduced expression of Hepcidin

Question 11

What are the diseases associated with iron homeostasis dysfunction?

Answer 11

Anaemia - Iron deficiency - reduction in haemoglobin and RBC - caused by increased iron demand, reduced iron uptake (diet/GI absorption), blood loss - symptoms revolve around body compensation for hypoxia (cardiac, cardiorespiratory, vascular constriction) - treated with iron tablets

Haemachromatosis - iron excess - toxicity in tissues