Reduction in frataxin causes progressive accumulation of mitochondrial damage
Abstract
Frataxin protein controls iron availability in mitochondria and reduced levels lead to the human disease, Friedreich's ataxia (FRDA). The molecular aspects of disease progression are not well understood. We developed a highly regulatable promoter system for expressing frataxin in yeast to address the consequences of chronically reduced amounts of this protein. Shutting off the promoter resulted in changes normally associated with loss of frataxin including iron accumulation within the mitochondria and the induction of mitochondrial petite mutants. While there was considerable oxidative damage to mitochondrial proteins, the petites were likely due to accumulation of mitochondrial DNA lesions and subsequent DNA loss. Chronically reduced frataxin levels resulted in similar response patterns. Furthermore, nuclear DNA damage was detected in a rad52 mutant, deficient in double-strand break repair. We conclude that reduced frataxin levels, which is more representative of the disease state, results in considerable oxidative damage in both mitochondrial and nuclear DNA.
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Deviations from normal iron levels have been indicated in the pathogenesis of aging, neurodegenerative disease, cancer, and infection.
“Deviations from normal iron levels have been indicated in the pathogenesis of aging, neurodegenerative disease, cancer, and infection (18, 23, 156, 180, 299, 334).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [156]
Aberrant levels of increased brain iron have been observed in Alzheimer disease and Parkinson disease.
“Furthermore, aberrant levels of increased brain iron have been observed in Alzheimer disease (AD) and Parkinson disease (PD) (23, 156).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [156]
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- Authors
- Karthikeyan, G.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Karthikeyan, G.
- ORCID
- Karthikeyan, G.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2003-11-04
- Volume
- 12
- Issue
- 24
- Pages
- 3331-3342
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2119863500
- Cited by
- 102
- References
- 67
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 2 · 2021: 1 · 2020: 2 · 2019: 5 · 2018: 2 · 2016: 4 · 2015: 1 · 2014: 4 · 2013: 2 · 2012: 5
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- frataxin, Friedreich's ataxia, mitochondrial iron accumulation, mitochondrial DNA damage, petite mutants, oxidative DNA damage, nuclear DNA damage, RAD52, DNA double-strand break repair, yeast model, mitochondrial DNA loss
- MeSH terms
- Frataxin, Cells, Cultured, DNA Damage, DNA-Binding Proteins, DNA, Mitochondrial, Mitochondria, Mutation, Oxidation-Reduction, Promoter Regions, Genetic, Saccharomyces cerevisiae, Down-Regulation, Saccharomyces cerevisiae Proteins, Iron-Binding Proteins, Rad52 DNA Repair and Recombination Protein
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