Clinical, biochemical and molecular genetic correlations in Friedreich's ataxia
Abstract
Friedreich's ataxia (FRDA) is an autosomal recessive disorder with a frequency of 1 in 50 000 live births. In 97% of patients it is caused by the abnormal expansion of a GAA repeat in intron 1 of the FRDA gene on chromosome 9, which encodes a 210 amino acid protein called frataxin. Frataxin is widely expressed and has been localized to mitochondria although its function is unknown. We have investigated mitochondrial function, mitochondrial DNA levels, aconitase activity and iron content in tissues from FRDA patients. There were significant reductions in the activities of complex I, complex II/III and aconitase in FRDA heart. Respiratory chain and aconitase activities were decreased although not significantly in skeletal muscle, but were normal in FRDA cerebellum and dorsal root ganglia, although there was a mild decrease in aconitase activity in the latter. Mitochondrial DNA levels were reduced in FRDA heart and skeletal muscle, although in skeletal muscle this was paralleled by a decline in citrate synthase activity. Increased iron deposition was seen in FRDA heart, liver and spleen in a pattern consistent with a mitochondrial location. The iron accumulation, mitochondrial respiratory chain and aconitase dysfunction and mitochondrial DNA depletion in FRDA heart samples largely paralleled those in the yeast YFH1 knockout model, suggesting that frataxin may be involved in mitochondrial iron regulation or iron sulphur centre synthesis. However, the severe deficiency in aconitase activity also suggests that oxidant stress may induce a self-amplifying cycle of oxidative damage and mitochondrial dysfunction, which may contribute to cellular toxicity.
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Both yeast and human frataxin are processed to a mature form in two sequential cleavage steps with a mitochondrial processing peptidase (MPP).
“It was shown that both yeast and human frataxin are processed to a mature form in two sequential cleavage steps with a mitochondrial processing peptidase (MPP) (28, 43, 167)”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [28]
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- Authors
- Bradley, J. L.
- Affiliations
- The Royal Free Hospital (GB)
- Corresponding author
- Bradley, J.L.
- ORCID
- Bradley, J.L.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-01-22
- Volume
- 9
- Issue
- 2
- Pages
- 275-282
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2140354171
- Cited by
- 339
- References
- 19
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 4 · 2023: 6 · 2022: 8 · 2021: 7 · 2020: 18 · 2019: 10 · 2018: 2 · 2017: 10 · 2016: 12 · 2015: 7 · 2014: 16 · 2013: 22 · 2012: 15
- FWCI
- 8.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- Friedreich's ataxia, frataxin, GAA repeat expansion, mitochondrial dysfunction, aconitase activity, mitochondrial DNA depletion, iron accumulation, respiratory chain complexes, citrate synthase, oxidative stress, heart, skeletal muscle, cerebellum, dorsal root ganglia
- MeSH terms
- Aconitate Hydratase, Adolescent, Adult, DNA, Mitochondrial, Electron Transport, Friedreich Ataxia, Humans, Iron, Middle Aged, Staining and Labeling
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