Frataxin, a mitochondrial protein known to participate in regulating cellular iron homeostasis, has recently been suggested to act as a mitochondrial iron chaperone for heme and Fe-S cluster biosynthesis. A reduced level of frataxin is the principal cause of the autosomal recessive neurodegenerative disorder Friedreich's ataxia (FRDA), which affects 1 in 50,000 humans. Frataxin has been shown to interact with the proteins that catalyze heme 2Fe-2S cluster production, suggesting frataxin plays a direct role in Fe-cofactor production. The interaction between yeast frataxin (Yfh1p) and the proteins Hem15p and Isu1p are believed to promote iron delivery and the cellular synthesis of heme and 2Fe-2S clusters, respectively, however almost nothing is known about how these proteins interact and how iron is delivered and transferred during complex formation. The objective of this application is to characterize frataxins role in both the heme and Fe-S cluster biosynthetic pathways. Our central hypothesis is that monomeric frataxins binds ferrous iron, protects the bound Fe(II) against oxidation in the potentially oxygen rich environment of the mitochondrion and then delivers reduced metal to target proteins involved in both the heme and Fe-S assembly pathways. This hypothesis is based on our laboratories biochemical and structural characterization of monomeric Yfh1p, as well as published reports of frataxins in vitro iron delivery activity. The rationale for our proposed studies is if we can distinguish frataxins role in regulating cellular iron homeostasis, we can help elucidate what pathways are deficient in FRDA patients, and we expect this information will lead to more successful treatment strategies for the disorder. We are in an excellent position to complete this work as we have recently cloned, expressed and solved the solution structure of yeast frataxin, and our laboratory has begun to characterize how Yfh1p binds iron and interacts with its protein binding partners. In addition, we have begun to test the physological significance of our findings both in vitro and in vivo.
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