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Iron-Dependent Self-Assembly of Recombinant Yeast Frataxin: Implications for Friedreich Ataxia
Open accessAbstract
Frataxin deficiency is the primary cause of Friedreich ataxia (FRDA), an autosomal recessive cardiodegenerative and neurodegenerative disease. Frataxin is a nuclear-encoded mitochondrial protein that is widely conserved among eukaryotes. Genetic inactivation of the yeast frataxin homologue (Yfh1p) results in mitochondrial iron accumulation and hypersensitivity to oxidative stress. Increased iron deposition and evidence of oxidative damage have also been observed in cardiac tissue and cultured fibroblasts from patients with FRDA. These findings indicate that frataxin is essential for mitochondrial iron homeostasis and protection from iron-induced formation of free radicals. The functional mechanism of frataxin, however, is still unknown. We have expressed the mature form of Yfh1p (mYfh1p) in Escherichia coli and have analyzed its function in vitro. Isolated mYfh1p is a soluble monomer (13,783 Da) that contains no iron and shows no significant tendency to self-associate. Aerobic addition of ferrous iron to mYfh1p results in assembly of regular spherical multimers with a molecular mass of approximately 1. 1 MDa (megadaltons) and a diameter of 13+/-2 nm. Each multimer consists of approximately 60 subunits and can sequester >3,000 atoms of iron. Titration of mYfh1p with increasing iron concentrations supports a stepwise mechanism of multimer assembly. Sequential addition of an iron chelator and a reducing agent results in quantitative iron release with concomitant disassembly of the multimer, indicating that mYfh1p sequesters iron in an available form. In yeast mitochondria, native mYfh1p exists as monomer and a higher-order species with a molecular weight >600,000. After addition of (55)Fe to the medium, immunoprecipitates of this species contain >16 atoms of (55)Fe per molecule of mYfh1p. We propose that iron-dependent self-assembly of recombinant mYfh1p reflects a physiological role for frataxin in mitochondrial iron sequestration and bioavailability.
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“Category 2 contained another 31 mutants with general growth defects that were independent of iron supplementation (Fig. 1b), including deletions of known and iron-associated genes (YFH1, ATM1) conserved in most fungi such as C. albicans (28, 29) and S. cerevisiae (30, 31).”
From A novel hybrid iron regulation network combines features from pathogenic and nonpathogenic yeasts (2016) · cites this paper as [30]
In the citing paper
“It was demonstrated that yeast mature frataxin directly binds iron (2), in which iron triggers assembly of frataxin oligomerization.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [2]
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Metadata
- Authors
- Adamec, J., Rusnak, F., Owen, W. G., Naylor, S., Benson, L. M., Gacy, A. M., & Isaya, G.
- Affiliations
- University of Minnesota Rochester (US)
- Mayo Clinic (US)
- Corresponding author
- Isaya, Grazia
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2000-09
- Volume
- 67
- Issue
- 3
- Pages
- 549-562
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC1287515
- OpenAlex
- W2080731376
- Cited by
- 255
- References
- 34
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 10 · 2018: 6 · 2017: 9 · 2016: 8 · 2015: 7 · 2014: 9 · 2013: 10 · 2012: 6
- FWCI
- 8.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG-15709, R01AG015709)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- frataxin, Friedreich's ataxia, mitochondrial iron homeostasis, iron sequestration, iron chelation, oxidative stress, iron bioavailability, recombinant protein expression
- MeSH terms
- Frataxin, Chromatography, Gel, Escherichia coli, Friedreich Ataxia, Homeostasis, Humans, Iron, Iron Chelating Agents, Microscopy, Electron, Mitochondria, Models, Biological, Molecular Sequence Data, Molecular Weight, Protein Binding, Recombinant Proteins, Saccharomyces cerevisiae, Solubility, Phosphotransferases (Alcohol Group Acceptor), Oxidative Stress, Microscopy, Atomic Force, Reducing Agents, Protein Structure, Quaternary, Iron-Binding Proteins
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