title: Hemin rescues adrenodoxin, heme a and cytochrome oxidase activity in frataxin-deficient oligodendroglioma cells.
abstract: Mutations in the frataxin gene cause neurodegeneration and demyelination in Friedreich's ataxia. We showed earlier that frataxin deficiency causes primary iron-sulfur cluster defects, and later causes defects in heme and cytochrome c hemoprotein levels. Iron-sulfur (Fe/S) clusters are required in two enzymes of heme biosynthesis in humans i.e. in ferrochelatase and adrenodoxin. However, decreases in ferrochelatase activity have not been observed in frataxin-deficient HeLa cells or patient lymphoblasts. We knocked down frataxin in oligodendroglioma cells using siRNA, which produced significant defects in the activity of the Fe/S cluster enzymes adrenodoxin and aconitase, the adrenodoxin product heme a, and cytochrome oxidase, for which heme a serves as a prosthetic group. Exogenous hemin produced a significant rescue of adrenodoxin, aconitase, heme a levels and cytochrome oxidase activity. Thus hemin rescues iron-sulfur cluster defects that are the result of frataxin-deficiency, perhaps as a consequence of increasing the pool of bioavailable iron, and thus should be more fully tested for beneficial effects in Friedreich's ataxia models.
authors.affiliation: Department of Molecular Biosciences, University of California, One Shields Avenue, Davis, CA 95616, USA.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Napoli
authors.forename: Dexter
authors.initials: D
authors.lastname: Morin
authors.forename: Rita
authors.initials: R
authors.lastname: Bernhardt
authors.forename: Alan
authors.initials: A
authors.lastname: Buckpitt
authors.forename: Gino
authors.initials: G
authors.lastname: Cortopassi
mesh_terms: D000325:Adrenodoxin / Q000378:metabolism*; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D003576:Electron Transport Complex IV / Q000378:metabolism*; D006367:HeLa Cells; D006418:Heme / Q000031:analogs & derivatives* / Q000378:metabolism; D006427:Hemin / Q000494:pharmacology*; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D009837:Oligodendroglioma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D000096923:Frataxin
chemical_list: D000325:Adrenodoxin; D017931:DNA Primers; D003576:Electron Transport Complex IV; D006418:Heme; D006427:Hemin; D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D000096923:Frataxin; C027728:heme a