title: Yeast and human frataxin are processed to mature form in two sequential steps by the mitochondrial processing peptidase.
abstract: Frataxin is a nuclear-encoded mitochondrial protein which is deficient in Friedreich's ataxia, a hereditary neurodegenerative disease. Yeast mutants lacking the yeast frataxin homologue (Yfh1p) show iron accumulation in mitochondria and increased sensitivity to oxidative stress, suggesting that frataxin plays a critical role in mitochondrial iron homeostasis and free radical toxicity. Both Yfh1p and frataxin are synthesized as larger precursor molecules that, upon import into mitochondria, are subject to two proteolytic cleavages, yielding an intermediate and a mature size form. A recent study found that recombinant rat mitochondrial processing peptidase (MPP) cleaves the mouse frataxin precursor to the intermediate but not the mature form (Koutnikova, H., Campuzano, V., and Koenig, M. (1998) Hum. Mol. Gen. 7, 1485-1489), suggesting that a different peptidase might be required for production of mature size frataxin. However, in the present study we show that MPP is solely responsible for maturation of yeast and human frataxin. MPP first cleaves the precursor to intermediate form and subsequently converts the intermediate to mature size protein. In this way, MPP could influence frataxin function and indirectly affect mitochondrial iron homeostasis.
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Branda
authors.forename: P
authors.initials: P
authors.lastname: Cavadini
authors.forename: J
authors.initials: J
authors.lastname: Adamec
authors.forename: F
authors.initials: F
authors.lastname: Kalousek
authors.forename: F
authors.initials: F
authors.lastname: Taroni
authors.forename: G
authors.initials: G
authors.lastname: Isaya
mesh_terms: D000595:Amino Acid Sequence; D001692:Biological Transport; D002451:Cell Compartmentation; D005609:Free Radicals / Q000378:metabolism; D005621:Friedreich Ataxia / Q000209:etiology; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism; D033862:Iron-Binding Proteins; D008666:Metalloendopeptidases / Q000378:metabolism*; D008969:Molecular Sequence Data; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012441:Saccharomyces cerevisiae; D013045:Species Specificity; D000096122:Mitochondrial Processing Peptidase; D000096923:Frataxin
chemical_list: D005609:Free Radicals; D007501:Iron; D033862:Iron-Binding Proteins; D008666:Metalloendopeptidases; D017853:Phosphotransferases (Alcohol Group Acceptor); D000096122:Mitochondrial Processing Peptidase; D000096923:Frataxin