Erythroid cells have a unique requirement for iron, which is incorporated into the heme component of hemoglobin. Mitochondria are essential for the metabolism of both iron and heme; the early and late steps of porphyrin biosynthesis occur in mitochondria and culminate in the intra-mitochondrial incorporation of iron into protoporphyrin IX to form heme. Mitochondria are also essential for the assembly of iron-sulfur complexes, which are important cofactors for a variety of enzymes that capture the oxidation-reduction potential of iron for catalytic purposes. At the present time, sparingly little is known about how iron and iron containing compounds enter and exit mammalian mitochondria. This is despite the fact that at any one time greater than 70% of the body's iron endowment has trafficked through prior to being incorporated into proteins. Our laboratory is interested in characterizing mitochondrial iron transport, particularly in erythroid cells. To explore this basic process, we are taking two approaches. First, we have characterized the protein defective in a strain of mouse, flexed-tail, that has an anemia associated with pathologic iron deposition in mitochondria, a so-called sideroblastic anemia. The flexed-tail protein is a mitochondrial multiple transmembrane protein of unknown function with homologues present in most eukaryotes, including yeast. Using yeast deficient in the sideroflexin homologue, we are studying the role of the flexed-tail protein in mitochondrial iron metabolism. Second, recent advances in yeast genetics have identified several genes important in yeast mitochondrial iron transport. Using transgenic technology, we are investigating the role of these proteins in mammalian mitochondria.