In a living organism, there are practically no ‘free’ metal ions in significant quantities, because they are toxic. In the liver (and other organs), iron accumulates NOT in a free form, but in a bound, non-toxic and bioavailable form.
Why is free iron dangerous?
Free iron ions (Fe2⁺ and Fe3⁺) in the cell act as a powerful oxidative stress catalyst (pro-oxidizer). They are involved in the Fenton reaction, during which extremely active and dangerous free radicals are formedthat damage the skin.:
Cell membrane lipids
Squirrels
DNA
This can lead to cell death and organ failure.
To prevent this from happening, the body has a special system for storing and transporting iron, where it is always associated with special proteinsProteins are high-molecular organic substances consisting of alpha-amino acids linked in a chain by a peptide bond. In living organisms, the amino acid composition of proteins is determined by the genetic code. During synthesis, 20 standard amino acids are used in most cases. Many combinations of them determine the great diversity of properties of protein molecules. Proteins play a key role in the immune response and can perform transport, storage, catalytic, structural, and receptor functions. Proteins are an important part of the nutrition of animals and humans. The main sources of proteins are meat, poultry, fish, milk, nuts, legumes, and grains..
The main forms of iron storage in the liver
Iron in the liver is stored in two main protein ‘containers’:
1. Ferritin (Main storage form)
It is the main and non-toxic protein depot of iron in our body.
Structure: Ferritin is similar to a hollow ball (nanometer ‘safe’), consisting of 24 subunits.
Capacity: Up to 4,500 iron atoms can be stored inside this ball in the form of a crystal of the mineral ferrihydrite [(FeO·OH)₈(FeO·H₂PO₄)].
Security: In this form, iron is physically isolated from cellular components and cannot participate in dangerous reactions.
Bioavailability: When the body needs iron (for example, to synthesize new red blood cells), it can be easily and quickly mobilized from ferritin.
It is the level of ferritin in the blood that is the main indicator of iron reserves in the body.
2. Hemosiderin (A form of ‘long-term’ and pathological accumulation)
Hemosiderin is a less organized and partially degraded polymer of ferritin and other iron-containing proteins.
Properties: It is less soluble, and iron mobilizes from it more slowly than from ferritin.
Value: A small amount of hemosiderin is normal. But its significant accumulation is observed during iron overload (hemochromatosis), when storage systems are overflowing. This is already considered a pathological condition that can damage the liver (fibrosis, cirrhosis).
The process of accumulation in the liver
Imagine the path of iron:
Suction: Iron is absorbed in the intestines (in the form of ions or heme) and enters the blood.
Transport: In the blood, it binds to the transport protein transferrin. , and there is practically no free iron in the plasma.
Delivery to the liver: Transferrin delivers iron to liver cells (hepatocytesHepatocytes are the main cells of the liver. They account for 60 to 80% of the mass of the entire organ. These are the main functional units of the liver, involved in a wide range of physiological processes such as nutrient metabolism, protein synthesis, detoxification, and bile secretion.).
Warehouse: In the liver cell, iron is ‘repackaged’ and placed in a ‘safe’ – a ferritin molecule.
What happens when there is an excess?
When iron supply chronically exceeds demand, the transferrin and ferritin system becomes overwhelmed.
First, the ferritin concentration increases.
Then hemosiderin begins to accumulate.
When these buffer systems also overflow, the so— called. Labile Iron Pool (LIP) can appear -this is a small pool of weakly bound iron ions in the cell, which is precisely the danger, triggering oxidative stress and tissue damage.
Total in the form of a table
Iron Form
Condition
Role and characteristics
Ferritin
Bound (in the protein “safe”)
The main, safe and bioavailable form of storage. The main indicator of iron reserves.
Hemosiderin
Bound (in protein aggregate)
‘In reserve’ and the pathological form. It accumulates when you are heavily overloaded with iron.
Labile pool (LIP)
Loosely coupled / ‘loose’
Dangerous, toxic form. There is always a small amount, but its growth leads to cell damage.
Transferrin
Associated (with transport protein)
A form of transport in the blood from the intestines and liver to the consumer organs.
Thereis no separate, special enzyme that would ‘decompose’ hemosiderin.
Instead, the body uses the process of autophagy to process hemosiderin. Let’s look at this in detail.
What is hemosiderin?
As we have already mentioned, hemosiderin is an unstable, partially degraded and denatured aggregate of ferritin protein, lipids, heme and other components. It is an insoluble precipitate inside the cell (in lysosomes). This is a ‘defective’ or ‘stale’ iron warehouse.
How does the body get rid of it?
The underlying mechanism is an extremely complex cellular process.
Capture of an aggregate (Autophagosome Formation):
The cell recognizes the accumulation of hemosiderin as a damaged or unnecessary component.
A double membrane structure called an autophagosome is formed around this aggregate. , which is like a ‘garbage bag’ that contains hemosiderin.
Enzymatic Degradation (Lysosomal Degradation):
The autophagosome fuses with the lysosome — a cellular organelle that is the’ stomach ‘ of the cell. The lysosome has a very acidic environment (pH ~4.5-5.0) and contains a set of powerful hydrolytic enzymesEnzymes are proteins that accelerate chemical reactions in the body. They ensure the occurrence of metabolic processes such as food digestion, energy release, cell formation, and many others.:
ProteasesProteases are enzymes that break down proteins. (e.g., cathepsins): break down the protein component of hemosiderin.
Lipases: they break down lipid inclusions.
Under the influence of this aggressive environment and enzymes, the protein ‘shell’ of hemosiderin is destroyed.
Iron release and recycling:
After the protein matrix is destroyed , iron atoms are released inside the lysosome.
Special transport proteins (for example, DMT1) ‘remove’ this iron from the lysosome back into the cytoplasm of the cell.
In the cytoplasm, this iron can be:
Re-packaged in new, functional ferritin.
It is used for the synthesis of iron-containing proteins (for example, hemoglobin).
Removed from the cell into the bloodstream with the ferroportin protein sothat transferrin can pick it up.
Why is hemosiderin so ‘persistent’?
The problem is that hemosiderin is a very dense, almost crystalline aggregate. Its structure makes it less accessible to the action of lysosomal enzymes compared to’ fresh ‘ ferritin. Imagine the difference between a fresh baguette and a dried cracker-the second is much more difficult to digest.
Because of this density, the process of its processing is slow. If iron enters the body faster than the old hemosiderin has time to be processed, it begins to accumulate.
What happens in pathology?
In diseases associated with iron overload (hemochromatosis), or with frequent blood transfusions, the autophagy system can not cope with the volume.
Hemosiderin accumulates in the cells of the liver, spleen, and pancreas.
Over time, this buildup leads to mechanical damage and oxidative stress (yet a small amount of iron can ‘leak out’), which causes fibrosis (scarring) and organ dysfunction.
Are there drugs that ‘degrade’ hemosiderin?
No, there is no pill that specifically breaks down hemosiderin. The main method of treatment for iron overload is bloodletting (phlebotomy) or the use of iron chelators.
Chelators (Deferoxamine, Deferasirox): These drugs do not ‘degrade’ hemosiderin. They bind free iron and iron, which is slowly released from ferritin and hemosiderin, forming a complex with it, which is then excreted in the urine and / or feces. They, in fact, ‘help’ the body to remove excess, reducing the overall load.
