Iron Goldilocks zone
Iron reactions with water producing free radicals
Most of the elemental iron that we eat is present in our body in the form of
Particularly rust sequestered in ferritin.
Low transferrin saturation
Overloaded transferrin saturation
High serum ferritin
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.
Major components of iron economy
60-70%: In erythrocytes as hemoglobin.
25%: In liver cells (hepatocytes and Kupffer cells) and macrophages as ferritin stores.
7.5%: In tissues
0.1%: As blood transferrin
~1% is recycled daily.
Iron steady state
Iron loss = Iron gain = 1-2 mg per day
~4g per adult male human body
Macrophage iron regulation
Intestinal Epithelium iron regulation
Reticulocyte iron regulation
Divalent metal transporter 1
How is secretion of iron regulated by liver and kidneys?
Only absorption is regulated, and it is regulated on the transcriptional level (upregulation of DMT1 and FPN1) and the mRNA stability level
Why is DMT1 upregulation insufficienct to absorb iron?
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
FPN1 expression in an iron replete vs iron deficient mouse
Duodenal iron staining in an iron replete vs iron deficient mouse
Note that in the replete condition the iron clusters in the location of the ferritin storage clusters.
The human body's iron sensor
How hepcidin regulates enterocytes
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)
What controls serum iron availability?
Each maturing erythrocyte needs approximately ____ iron atoms before it is mature.
Each maturing erythrocyte needs approximately 3 billion iron atoms before it is mature.
Transferrin cycle in a maturing erythrocyte
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.
Negative feedback. . .
This is the easiest way to remember positive vs negative feedback.
In cases of iron toxicity, how are erythrocytes affected?
Heme synthesis in erythrocytes is found to be normal to high, but the number of erythrocytes is totally unaffected.
In FPN1 loss of function, hepcidin levels are found to be
paradoxically. Possibly because iron stores in the hepatocytes are still great despite low circulating iron.
If there is more iron in macrophages than hepatocytes, think
FPN1 loss of function
How do you treat iron toxicity?