title: Frataxin-bypassing Isu1: characterization of the bypass activity in cells and mitochondria.
abstract: Frataxin is a conserved mitochondrial protein, and deficiency underlies the neurodegenerative disease Friedreich's ataxia. Frataxin interacts with the core machinery for Fe-S cluster assembly in mitochondria. Recently we reported that in frataxin-deleted yeast strains, a spontaneously occurring mutation in one of two genes encoding redundant Isu scaffold proteins, bypassed the mutant phenotypes. In the present study we created strains expressing a single scaffold protein, either Isu1 or the bypass mutant M107I Isu1. Our results show that in the frataxin-deletion strain expressing the bypass mutant Isu1, cell growth, Fe-S cluster protein activities, haem proteins and iron homoeostasis were restored to normal or close to normal. The bypass effects were not mediated by changes in Isu1 expression level. The persulfide-forming activity of the cysteine desulfurase was diminished in the frataxin deletion (∆yfh1 ISU1) and was improved by expression of the bypass Isu1 (∆yfh1 M107I ISU1). The addition of purified bypass M107I Isu1 protein to a ∆yfh1 lysate conferred similar enhancement of cysteine desulfurase as did frataxin, suggesting that this effect contributed to the bypass mechanism. Fe-S cluster-forming activity in isolated mitochondria was stimulated by the bypass Isu1, albeit at a lower rate. The rescuing effects of the bypass Isu1 point to ways that the core defects in Friedreich's ataxia mitochondria can be restored.
authors.affiliation: *Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
authors.forename: Heeyong
authors.initials: H
authors.lastname: Yoon
authors.affiliation: *Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
authors.forename: Simon A B
authors.initials: SA
authors.lastname: Knight
authors.affiliation: †Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, NJ 07101, U.S.A.
authors.forename: Alok
authors.initials: A
authors.lastname: Pandey
authors.affiliation: †Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, NJ 07101, U.S.A.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Pain
authors.affiliation: *Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: †Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, NJ 07101, U.S.A.
authors.forename: Debkumar
authors.initials: D
authors.lastname: Pain
authors.affiliation: *Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, U.S.A.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dancis
mesh_terms: D017353:Gene Deletion; D007501:Iron / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D000096923:Frataxin
chemical_list: D007501:Iron; D033862:Iron-Binding Proteins; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D000096923:Frataxin; C121520:ISU1 protein, S cerevisiae