Schematic illustration of heme and cluster synthesis and metabolism. (A) Schematic illustration of normal heme and [Fe-S] cluster synthesis, (B) PIX induction of heme synthesis and the inhibition of frataxin (Fxn) expression and [Fe-S] cluster metabolism, and (C) a proposed mechanism of the disrupted mitochondrial [Fe-S] cluster biosynthesis and Fe metabolism in Friedreich ataxia (FA). (A) Under physiologic conditions, Fe is used for the synthesis of heme or the genesis of [Fe-S] clusters. (B) PIX has been shown to decrease frataxin expression and we hypothesize that frataxin acts as a PIX-sensitive metabolic switch that regulates the use of Fe for heme synthesis. In this way, increased PIX levels indicate a requirement for heme synthesis that decreases frataxin expression and results in diversion of Fe to this pathway from [Fe-S] cluster assembly or Fe storage. Hence, we propose that this may be the role for frataxin under physiologic conditions. (C) Since frataxin expression is low in FA, [Fe-S] cluster synthesis is impaired. Moreover, because there is no intense demand for heme synthesis in nonerythroid tissues, the excess Fe not used for [Fe-S] cluster synthesis is incorporated into m-Ferr. Initially, the Fe accumulation in m-Ferr may be protective and would explain the delay in pathogenesis of FA until many years after birth. However, in the absence of marked Fe utilization in nonerythroid cells for the generation of heme, the m-Ferr may degrade to “hemosiderin-like” material that is redox-active and could lead to the mitochondrial damage observed in FA.