title: Mutation in the Fe-S scaffold protein Isu bypasses frataxin deletion.
abstract: Frataxin is a conserved mitochondrial protein deficient in patients with Friedreich's ataxia. Frataxin has been implicated in control of iron homoeostasis and Fe-S cluster assembly. In yeast or human mitochondria, frataxin interacts with components of the Fe-S cluster synthesis machinery, including the cysteine desulfurase Nfs1, accessory protein Isd11 and scaffold protein Isu. In the present paper, we report that a single amino acid substitution (methionine to isoleucine) at position 107 in the mature form of Isu1 restored many deficient functions in Δyfh1 or frataxin-depleted yeast cells. Iron homoeostasis was improved such that soluble/usable mitochondrial iron was increased and accumulation of insoluble/non-usable iron within mitochondria was largely prevented. Cytochromes were returned to normal and haem synthesis was restored. In mitochondria carrying the mutant Isu1 and no frataxin, Fe-S cluster enzyme activities were improved. The efficiency of new Fe-S cluster synthesis in isolated mitochondria was markedly increased compared with frataxin-negative cells, although the response to added iron was minimal. The M107I substitution in the highly conserved Isu scaffold protein is typically found in bacterial orthologues, suggesting that a unique feature of the bacterial Fe-S cluster machinery may be involved. The mechanism by which the mutant Isu bypasses the absence of frataxin remains to be determined, but could be related to direct effects on Fe-S cluster assembly and/or indirect effects on mitochondrial iron availability.
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Heeyong
authors.initials: H
authors.lastname: Yoon
authors.forename: Ramesh
authors.initials: R
authors.lastname: Golla
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Lesuisse
authors.forename: Jayashree
authors.initials: J
authors.lastname: Pain
authors.forename: Jason E
authors.initials: JE
authors.lastname: Donald
authors.forename: Elise R
authors.initials: ER
authors.lastname: Lyver
authors.forename: Debkumar
authors.initials: D
authors.lastname: Pain
authors.forename: Andrew
authors.initials: A
authors.lastname: Dancis
mesh_terms: D019943:Amino Acid Substitution; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal / Q000502:physiology; D007501:Iron / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000235:genetics / Q000378:metabolism*; D008291:Malate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D000096923:Frataxin
chemical_list: D007501:Iron; D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D008291:Malate Dehydrogenase; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D000096923:Frataxin; C121520:ISU1 protein, S cerevisiae