Figure 1.

A general scheme of cellular iron traffic. Iron can enter cells both as TBI (transferrin-bound iron) or as NTBI (non-transferrin-bound iron). Iron-loaded transferrin binds to its ubiquitous receptor TFRC (and in some cell types to TFR2) on the cell membrane and the complex is endocytosed. The endosome is acidified, iron is released from TF and poured into cytoplasm through divalent metal transporter 1 (DMT1), and possibly through ZIP14 and type IV mucolipidosis-associated protein TRPML1. The empty complex dissociates and is then recycled outside the cell for a new transport cycle. NTBI circulates in the plasma as Fe³⁺ in low-molecular weight complexes or bound to albumin. After a reduction step, it is taken up as Fe²⁺ through different importers, depending on the cell type: ZIP14, ZIP8, DMT1, LTCCs (L-type Ca²⁺ channels), TTCCs (T-type Ca²⁺ channels). ZIP8 and ZIP14 are also present on lysosomal, mitochondrial, and endosomal membranes. Iron trafficking in the cytosol is mediated by PCBP1/2 (poly(rC) binding protein 1/2), which cargos the metal to ferritin (FT), the iron storage protein, and to other iron-containing enzymes (not shown). In the mitochondrion, the main iron-transport systems are constituted by mitoferrin 1/2 (MFRN) on the inner membrane, and by DMT1 and ZIP8 on the outer membrane. Ferritin iron stores are mobilized through the action of Nuclear Receptor Coactivator 4 (NCOA4), which directs ferritin to the lysosome for degradation. Lysosomes pour iron into cytoplasm through at least four exporters (ZIP8, ZIP14, DMT1 and TRPML1). Cellular iron export is mediated by ferroportin (FPN), which acts in concert with a multicopper ferroxidase (CP, ceruloplasmin or HEPH hephaestin, depending on the cell type).