title: Assembly of human frataxin is a mechanism for detoxifying redox-active iron.
abstract: Mitochondrial function depends on a continuous supply of iron to the iron-sulfur cluster (ISC) and heme biosynthetic pathways as well as on the ability to prevent iron-catalyzed oxidative damage. The mitochondrial protein frataxin plays a key role in these processes by a novel mechanism that remains to be fully elucidated. Recombinant yeast and human frataxin are able to self-associate in large molecular assemblies that bind and store iron as a ferrihydrite mineral. Moreover, either single monomers or polymers of human frataxin have been shown to serve as donors of Fe(II) to ISC scaffold proteins, oxidatively inactivated [3Fe-4S](+) aconitase, and ferrochelatase. These results suggest that frataxin can use different molecular forms to accomplish its functions. Here, stable monomeric and assembled forms of human frataxin purified from Escherichia coli have provided a tool for testing this hypothesis at the biochemical level. We show that human frataxin can enhance the availability of Fe(II) in monomeric or assembled form. However, the monomer is unable to prevent iron-catalyzed radical reactions and the formation of insoluble ferric iron oxides. In contrast, the assembled protein has ferroxidase activity and detoxifies redox-active iron by sequestering it in a protein-protected compartment.
authors.affiliation: Department of Pediatric Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Heather A
authors.initials: HA
authors.lastname: O'Neill
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Gakh
authors.forename: Sungjo
authors.initials: S
authors.lastname: Park
authors.forename: Jin
authors.initials: J
authors.lastname: Cui
authors.forename: Steven M
authors.initials: SM
authors.lastname: Mooney
authors.forename: Matthew
authors.initials: M
authors.lastname: Sampson
authors.forename: Gloria C
authors.initials: GC
authors.lastname: Ferreira
authors.forename: Grazia
authors.initials: G
authors.lastname: Isaya
mesh_terms: D001682:Biological Availability; D002570:Ceruloplasmin / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage; D005290:Ferric Compounds / Q000737:chemistry / Q000378:metabolism; D005296:Ferrous Compounds / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D007501:Iron / Q000378:metabolism* / Q000633:toxicity*; D033862:Iron-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000737:chemistry / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000378:metabolism*; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012996:Solutions; D000096923:Frataxin
chemical_list: D002570:Ceruloplasmin; D005290:Ferric Compounds; D005296:Ferrous Compounds; D007501:Iron; D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D020033:Protein Isoforms; D011994:Recombinant Proteins; D012996:Solutions; D000096923:Frataxin