Iron Transport

Question 1

Iron Goldilocks zone

Answer 1

Question 2

Fenton chemistry

Answer 2

Iron reactions with water producing free radicals

Question 3

Most of the elemental iron that we eat is present in our body in the form of

Answer 3

rust!

Particularly rust sequestered in ferritin.

Question 4

Transferrin

Answer 4

Question 5

Ferritin

Answer 5

Question 6

Low transferrin saturation

Answer 6

Iron deficiency

Question 7

Overloaded transferrin saturation

Answer 7

iron toxicity

Question 8

High serum ferritin

Answer 8

Ferritin is primarily a cellular protein.

However, some ferritin leaks in the blood and thus high serum ferritin can be associated with iron overload. Other diseases of the liver can also cause elevated serum ferri:n.

Question 9

Major components of iron economy

Answer 9

60-70%: In erythrocytes as hemoglobin.

25%: In liver cells (hepatocytes and Kupffer cells) and macrophages as ferritin stores.

7. 5%: In tissues
8. 1%: As blood transferrin

~1% is recycled daily.

Question 10

Iron steady state

Answer 10

Iron loss = Iron gain = 1-2 mg per day

~4g per adult male human body

Question 11

Macrophage iron regulation

Answer 11

Question 12

Intestinal Epithelium iron regulation

Answer 12

Question 13

Reticulocyte iron regulation

Answer 13

Question 14

DMT1

Answer 14

Divalent metal transporter 1

Question 15

FPN1

Answer 15

Ferroportin 1

Question 16

How is secretion of iron regulated by liver and kidneys?

Answer 16

It’s not!!!!!!!

Only absorption is regulated, and it is regulated on the transcriptional level (upregulation of DMT1 and FPN1) and the mRNA stability level

Question 17

Why is DMT1 upregulation insufficienct to absorb iron?

Answer 17

Without FPN1 upregulation as well, the iron cannot diffuse into the lamina propria in a timely manner before the enterocyte is sloughed off and the iron is lost

Question 18

FPN1 expression in an iron replete vs iron deficient mouse

Answer 18

Question 19

Duodenal iron staining in an iron replete vs iron deficient mouse

Answer 19

Note that in the replete condition the iron clusters in the location of the ferritin storage clusters.

Question 20

Hepcidin

Answer 20

Question 21

The human body’s iron sensor

Answer 21

Question 22

How hepcidin regulates enterocytes

Answer 22

Hepcidin binds to FPN1 directly via the basolateral surface of enterocytes. It induces phosphorylation and endocytosis. The endocytosed FPN1 is ubiquitinated and targeted for lysosomal degradation (NOT proteasomal)

Question 23

What controls serum iron availability?

Answer 23

Question 24

Each maturing erythrocyte needs approximately ____ iron atoms before it is mature.

Answer 24

Each maturing erythrocyte needs approximately 3 billion iron atoms before it is mature.

Question 25

Transferrin cycle in a maturing erythrocyte

Answer 25

Once mature, erythrocytes cease to produce Transferrin receptor and eventually lose all expression.

Note that transferrin loses its affinity for iron at the low pH of the lysosome!

Also note that heme metabolism takes place in the mitochondrial matrix.

Question 26

Negative feedback. . .

Answer 26

resists change.

This is the easiest way to remember positive vs negative feedback.

Question 27

In cases of iron toxicity, how are erythrocytes affected?

Answer 27

Heme synthesis in erythrocytes is found to be normal to high, but the number of erythrocytes is totally unaffected.

Question 28

In FPN1 loss of function, hepcidin levels are found to be

Answer 28

HIGH

paradoxically. Possibly because iron stores in the hepatocytes are still great despite low circulating iron.

Question 29

If there is more iron in macrophages than hepatocytes, think

Answer 29

FPN1 loss of function

Question 30

How do you treat iron toxicity?

Answer 30

Phlebotomy

Question 31

How do you treat FPN1 LoF-mediated iron deficiency

Answer 31

Phlebotomy, but carefully observed phlebotomy.

The problem with FPN1 LoF is that there is a low level of circulating iron, but iron toxicity in the tissues.

Question 32

Why does ferritin associate with both iron oxidases and iron reductases?

Answer 32

An oxidase must oxidize Iron II that comes through FPN1 to Iron III in order for it to bind to transferrin or ferritin. In order to remove Fe III from the ferritin lattice, it must be reduced to Fe II, which can no longer bind.

Question 33

HFE loss of function mutation

Answer 33

HFE is part of the iron sensing apparatus on hepatocytes. If HFE loses function, iron cannot be detected, and as such hepatocytes stop all Hepcidin transcription in order to signal to the body to acquire more iron.

This leads to chronic iron toxicity.

Question 34

Hereditary Hemachromatosis

Answer 34