Free Fe²⁺ in a cell makes hydroxyl radicals through the Fenton reaction, which attack DNA, proteins and lipids, so the body must lock iron inside the cage.Free Fe²⁺ inside a cell is an extremely dangerous reactant:
Fenton reaction: Fe²⁺ + H₂O₂ → Fe³⁺ + •OH + OH⁻
The hydroxyl radical (•OH) generated is the most reactive radical known, with a half-life < 1 ns; it immediately attacks DNA / proteins / lipids — one •OH, in the instant it exists, can destroy an entire organelle.
So the body must never let large amounts of free Fe²⁺ wander inside cells. At any time intracellular free Fe²⁺ < 1 µmol/L, while total iron (mostly bound by various iron proteins) can be as high as 10-50 µmol/L.
This is why the cage exists — to lock iron away safely.
2 · 24-subunit hollow cage
is a hollow sphere of 24 H and L subunits: H chains oxidize incoming Fe²⁺ to Fe³⁺, and L chains let it mineralize inside the cage. is a hollow spherical protein self-assembled from 24 subunits:
· Diameter ~ 12 nm, inner cavity diameter ~ 8 nm · The 24 subunits are a mix of H chains + L chains, with the ratio varying by tissue · H (heavy) chain has ferroxidase activity (ferroxidase site) → oxidizes incoming Fe²⁺ to Fe³⁺ · L (light) chain provides nucleation sites → lets Fe³⁺ crystallize and mineralize inside the cage · The cage wall has 3- and 4-fold symmetric channels → controlling iron entry and exit
This geometry of limited flux lets ferritin both store and release iron — like a metal safe with an automatic door.
3 · Stores up to ~4500 Fe atoms
Iron entering the cage is oxidized and mineralized into a core of up to about 4500 atoms, and the little that leaks into blood correlates with tissue iron stores.Fe²⁺ enters the cage through the symmetric channels:
1. Once inside, H chains immediately oxidize it to Fe³⁺ (reducing Fenton risk) 2. Fe³⁺ is nucleated by L chains inside the cage → forms a mineral core — mainly hydrated iron phosphate (similar to rust) 3. Continuous loading; one ferritin cage holds up to ~ 4500 iron atoms
This is why serum ferritin is the most sensitive indicator of stored iron — small amounts of ferritin that leak from cells into blood correlate positively with tissue iron stores:
· Ferritin < 15 µg/L → store is essentially empty · Ferritin < 30 → clinical "iron deficiency without anemia" · Ferritin > 300 → elevated — but think inflammation / liver disease / metabolic syndrome first; this number alone cannot establish iron overload · Transferrin saturation > 45% AND ferritin > 200 (men and women who no longer menstruate) / 150 (menstruating women) → time to see a doctor about hemochromatosis, usually followed by HFE genotyping; the two ferritin numbers are the WHO 2020 line for iron-overload risk in otherwise healthy adults
Note: ferritin is also an acute-phase reactant and rises in inflammation — so with chronic inflammation + truly low iron stores, ferritin can appear normal on the surface while iron deficiency is actually present; and conversely, the most common explanation for a high ferritin is inflammation, not iron overload.
4 · Release on demand · ferritinophagy
When iron is needed, releases it through its channels or NCOA4 sends the whole cage to the lysosome, and a new protein catches the freed Fe²⁺ at once.When the body needs iron (erythropoiesis, menstruation, pregnancy, hypoxic stress) → releases iron:
· Classic mechanism: cage channels partially open → Fe³⁺ reduced to Fe²⁺ → flows out through the channel (regulated by IRP1/2) · Modern mechanism: ferritinophagy — the selective-autophagy protein NCOA4 sends the entire ferritin cage into the lysosome for degradation → iron is released in one shot
The released Fe²⁺ is immediately picked up by a new protein — never allowed to drift free — and may go on to: · Enter the mitochondria for heme synthesis (red blood cells) · Enter iron-sulfur cluster (Fe-S cluster) synthesis (electron transport chain) · Leave the cell (via ferroportin) and re-enter circulation (regulated by hepcidin; see iron/gut)
The elegance of the whole design: iron is always in the hands of some protein, never "free iron" running loose. This is the precise balance between avoiding Fenton chemistry and supporting normal physiology — one of the body's most elegant pieces of engineering.