Cited by 184Mitochondrial Function and PathologyGenetic Neurodegenerative DiseasesNeurological diseases and metabolism

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Mitochondrial iron detoxification is a primary function of frataxin that limits oxidative damage and preserves cell longevity

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Gakh, Oleksandr, Park, Sungjo, Liu, Gang, Macomber, Lee, Imlay, James A., Ferreira, Gloria C., Isaya, Grazia·2006·Human Molecular Genetics

DOI 10.1093/hmg/ddi461

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Abstract

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.

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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
ORCID: Gakh, Oleksandr
Park, Sungjo
Imlay, James A.
Isaya, Grazia
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
DOI: 10.1093/hmg/ddi461
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

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Mitochondrial iron detoxification is a primary function of frataxin that limits oxidative damage and preserves cell longevity

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