The DOI matches its Crossref record; 59 of the 59 references it cites were found in a registry or an index.
Mitochondrial iron detoxification is a primary function of frataxin that limits oxidative damage and preserves cell longevity
Open accessAbstract
Friedreich ataxia is a severe autosomal-recessive disease characterized by neurodegeneration, cardiomyopathy and diabetes, resulting from reduced synthesis of the mitochondrial protein frataxin. Although frataxin is ubiquitously expressed, frataxin deficiency leads to a selective loss of dorsal root ganglia neurons, cardiomyocytes and pancreatic beta cells. How frataxin normally promotes survival of these particular cells is the subject of intense debate. The predominant view is that frataxin sustains mitochondrial energy production and other cellular functions by providing iron for heme synthesis and iron-sulfur cluster (ISC) assembly and repair. We have proposed that frataxin not only promotes the biogenesis of iron-containing enzymes, but also detoxifies surplus iron thereby affording a critical anti-oxidant mechanism. These two functions have been difficult to tease apart, however, and the physiologic role of iron detoxification by frataxin has not yet been demonstrated in vivo. Here, we describe mutations that specifically impair the ferroxidation or mineralization activity of yeast frataxin, which are necessary for iron detoxification but do not affect the iron chaperone function of the protein. These mutations increase the sensitivity of yeast cells to oxidative stress, shortening chronological life span and precluding survival in the absence of the anti-oxidant enzyme superoxide dismutase. Thus, the role of frataxin is not limited to promoting ISC assembly or heme synthesis. Iron detoxification is another function of frataxin relevant to anti-oxidant defense and cell longevity that could play a critical role in the metabolically demanding environment of non-dividing neuronal, cardiac and pancreatic beta cells.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“lowering iron does increase the lifespan of Drosophila [1215] and yeast [1105].”
From Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases (2009) · cites this paper as [1105]
In the citing paper
“The mRNA of hepcidin does not contain this element (99),”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [99]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Friedreich's Ataxia: Autosomal Recessive Disease Caused by an Intronic GAA Triplet Repeat Expansion
Campuzano, V., Montermini, L., Moltò, M. D., Pianese, L., Cossée, M., Cavalcanti, F., Monros, E., Rodius, F., Duclos, F., Monticelli, A., et al. (1996) · Science · doi:10.1126/science.271.5254.1423 · Cited by 2,786
Iron, brain ageing and neurodegenerative disorders
Zecca, L., Youdim, M. B. H., Riederer, P., Connor, J. R., & Crichton, R. R. (2004) · Nature Reviews Neuroscience · doi:10.1038/nrn1537 · Cited by 1,801
Oxidative DNA damage and disease: induction, repair and significance
Evans, M. D., Dizdaroglu, M., & Cooke, M. S. (2004) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2003.11.001 · Cited by 1,372
Mineralization in ferritin: an efficient means of iron storage
Chasteen, N. D., & Harrison, P. M. (1999) · Journal of Structural Biology · doi:10.1006/jsbi.1999.4118 · Cited by 815
Sturtz, L. A., Diekert, K., Jensen, L. T., Lill, R., & Culotta, V. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105296200 · Cited by 735
Superoxide Dismutase Activity Is Essential for Stationary Phase Survival in Saccharomyces cerevisiae
Longo, V. D., Gralla, E. B., & Valentine, J. S. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.21.12275 · Cited by 531
Frataxin Acts as an Iron Chaperone Protein to Modulate Mitochondrial Aconitase Activity
Bulteau, A.-L., O’Neill, H. A., Kennedy, M. C., Ikeda‐Saito, M., Isaya, G., & Szweda, L. I. (2004) · Science · doi:10.1126/science.1098991 · Cited by 372
Self-citationYoon, T., & Cowan, J. A. (2003) · Journal of the American Chemical Society · doi:10.1021/ja027967i · Cited by 353
An interaction between frataxin and Isu1/Nfs1 that is crucial for Fe/S cluster synthesis on Isu1
Gerber, J., Mühlenhoff, U., & Lill, R. (2003) · EMBO Reports · doi:10.1038/sj.embor.embor918 · Cited by 334
The yeast frataxin homolog Yfh1p plays a specific role in the maturation of cellular Fe/S proteins
Mühlenhoff, U. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.17.2025 · Cited by 326
Cited by
Sorted by citations
Mitochondrial membrane permeabilization in cell death
Kroemer, G., Galluzzi, L., & Brenner, C. (2007) · Physiological Reviews · doi:10.1152/physrev.00013.2006 · Cited by 3,598
Kell, D. B. (2009) · BMC Medical Genomics · doi:10.1186/1755-8794-2-2 · Cited by 554
Intracellular iron transport and storage: from molecular mechanisms to health implications
Mackenzie, E. L., Iwasaki, K., & Tsuji, Y. (2008) · Antioxidants & Redox Signaling · doi:10.1089/ars.2007.1893 · Cited by 526
Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases
Trushina, E. V., & McMurray, C. T. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2006.10.056 · Cited by 451
Selective iron chelation in Friedreich ataxia: biologic and clinical implications
Boddaert, N., Le Quan Sang, K. H., Rötig, A., Leroy-Willig, A., Gallet, S., Brunelle, F., Sidi, D., Thalabard, J.-C., Munnich, A., & Cabantchik, Z. I. (2007) · Blood · doi:10.1182/blood-2006-12-065433 · Cited by 409
Metadata
- Authors
- Gakh, O., Park, S., Liu, G., Macomber, L., Imlay, J. A., Ferreira, G. C., & Isaya, G.
- Affiliations
- Mayo Clinic (US)
- University of Illinois Urbana-Champaign (US)
- Corresponding author
- Gakh, Oleksandr
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-12-21
- Volume
- 15
- Issue
- 3
- Pages
- 467-479
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2115953418
- Cited by
- 184
- References
- 59
- Citations by year
- 2026: 2 · 2024: 4 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 1 · 2019: 5 · 2018: 7 · 2017: 10 · 2016: 4 · 2015: 6 · 2014: 9 · 2013: 13 · 2012: 10
- FWCI
- 7.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Human Molecular Genetics (publishedVersion, other-oa)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- American Cancer Society
- Friedreich's Ataxia Research Alliance
- National Institutes of Health (GM49640)
- National Institute on Aging (AG-15709, R01AG015709)
- National Institute of General Medical Sciences (R01GM049640, GM 49640)
- 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, iron mineralization, oxidative stress, chronological lifespan, superoxide dismutase, iron chaperone, iron-sulfur cluster assembly, heme biosynthesis, cell longevity, antioxidant defense
- MeSH terms
- Frataxin, Amino Acids, Ceruloplasmin, Iron, Inactivation, Metabolic, Minerals, Mitochondria, Mutation, Saccharomyces cerevisiae, Superoxide Dismutase, Mutagenesis, Site-Directed, Oxidative Stress, Molecular Chaperones, Iron-Binding Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
