Fig. 4: Cartoon depicting an example of iron uptake and utilization in mitochondria.

Clathrin-coated endosomes containing TfR1-bound iron are endocytosed. The endosome lumen is acidified by a proton pump; the acidification decreases Tf-iron binding affinity, and as consequence, iron is released into the endosome lumen. Here, ferric ions are reduced by Steap2 and released through DMT1 into the cell cytosol. TfR1 is recycled back to the plasma membrane by recycling endosomes. Cytosolic free iron enters mitochondria through the mitoferrin channels. A second mechanism, called Kiss&Run, has been described to deliver iron to mitochondria, which consists of transient fusion between endosomes and mitochondrial membranes. Inside the mitochondrion, the labile iron pool (mitLIP), the redox-active form of iron, is used for sustaining heme and ISC biosynthesis or stored in mitochondrial ferritin (mtFt).