The developing erythron requires tremendous amounts of iron (Fe) for the synthesis of heme for hemoproteins, such as hemoglobin, and iron-sulfur (Fe/S) clusters of proteins, which are required to catalyze redox reactions and regulate Fe uptake and storage. The uptake of Fe from transferrin (Tf) involves the binding of Tf to its cognate receptor (TfR), followed by the endocytosis of the Tf-TfR complex.1,2 In the late endosome, the release of Fe3+ from TfR is achieved by acidification of the vesicle by the v-ATPase H+-pump. Steap3 reduces the liberated Fe3+ prior to its transport out of the endosome by the DMT1 transporter. In contrast to previous conventional models for a cytosolic intermediate state, new data have emerged showing the direct interorganellar transfer of Fe from the endosome to the mitochondria.3 Although it is assumed that the exported Fe is targeted to the mitochondria for eventual incorporation into heme and Fe/S clusters, our understanding of the precise mechanism of how Fe traverses the outer and inner mitochondrial membranes remains poorly understood. Work in yeast mutants have implicated the role of solute carriers, Mrs3/4p, in mitochondrial iron homeostasis and revealed that it is the reduced form of iron, Fe2+, that is imported into the mitochondria. Subsequent studies of the zebrafish mutant, frascati, led to the discovery of mitoferrin 1 (Mfrn1, slc25a37), the vertebrate ortholog of Mrs3/4, as the major iron importer across the inner mitochondrial membrane in developing erythroblasts.4 A structurally related paralog, mitoferrin 2 (Mfrn2, slc25a28), plays the analogous role of Fe importer in non-erythroid cells. Loss-of-function studies of Mfrn1 in the mouse have confirmed its requirement in mammalian primitive and definitive erythropoiesis and its essential role in heme and Fe/S biosynthesis. Several questions remain unanswered in mitochondrial Fe metabolism:
Do the two Mfrn importers account for all Fe imported into the mitochondria? How does Fe get across the outer mitochondrial membrane to reach the Mfrn importers? How does the translocated Fe in the matrix ultimately reach ferrochelatase to form heme? How is Fe translocated across the inner mitochondrial membrane?
Quantification of active mitochondrial permeability transition pores using GNX-4975 inhibitor titrations provides insights into molecular identity