Figure 2. Cellular iron homeostasis.

Depicted cell is an amalgam of many cell types; not all proteins/pathways are present in all cells. Iron enters into cells primarily by transferrin receptor 1 (TFR1)-mediated endocytosis. In endosomes, iron is freed from TF and reduced by a ferriductase (STEAP3) before exiting into the cytosol via divalent metal transporter (DMT1). TF and TFR1 are recycled back to the cell membrane for further cycles. DMT1 and other transporters (ZIP8, ZIP14) function in non-TF bound iron (NTBI) uptake pathways in some cell types. Other iron acquisition pathways in some cell types include uptake of hemoglobin(Hb)-haptoglobin, heme-hemopexin, heme, lipocalin 2, and ferritin via CD163, CD91, FLVCR2, SLC22A17, SCARA5, and TIM2 receptors respectively. In the cytosol, iron enters the labile iron pool (LIP), and is then utilized, stored, or exported out of the cell. Cytoplasmic iron transport is assisted in some cases by the chaperone poly (rC) binding protein 1 (PCBP1). Iron is mainly utilized by mitochondria for heme synthesis and iron-sulfur clusters (ISCs) biogenesis, with mitoferrins (MFRN1/2) playing a role in mitochondrial iron import and FLVCR1B playing a role in mitochondrial heme export. Excess iron in the cytosol is stored safely in ferritin. A mitochondrial form of ferritin (MTFT) is also expressed in some cell types. When the demand arises, ferritin can be targeted for autophagic turnover by nuclear receptor coactivator 4 (NCOA4) to release iron into the cytosolic LIP. Iron is exported out of the cell by ferroportin (FPN), assisted by ferroxidases ceruloplasmin (CP)/hephaestin (HP), followed by iron loading onto TF. FLVCR1A may play a role in heme export in some cell types.