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Cited by 219Genetic Neurodegenerative DiseasesMitochondrial Function and PathologyNeurological diseases and metabolism

Friedreich ataxia: the oxidative stress paradox

Seznec, Hervé, Simon, Delphine, Bouton, Cécile, Reutenauer, Laurence, Hertzog, Ariane, Golik, Pawel, Procaccio, Vincent, Patel, Manisha +3 more·2005·Human Molecular Genetics
DOI 10.1093/hmg/ddi042
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Abstract

Friedreich ataxia (FRDA) results from a generalized deficiency of mitochondrial and cytosolic iron-sulfur protein activity initially ascribed to mitochondrial iron overload. Recent in vitro data suggest that frataxin is necessary for iron incorporation in Fe-S cluster (ISC) and heme biosynthesis. In addition, several reports suggest that continuous oxidative damage resulting from hampered superoxide dismutases (SODs) signaling participates in the mitochondrial deficiency and ultimately the neuronal and cardiac cell death. This has led to the use of antioxidants such as idebenone for FRDA therapy. To further discern the role of oxidative stress in FRDA pathophysiology, we have tested the potential effect of increased antioxidant defense using an MnSOD mimetic (MnTBAP) and Cu,ZnSOD overexpression on the murine FRDA cardiomyopathy. Surprisingly, no positive effect was observed, suggesting that increased superoxide production could not explain by itself the FRDA cardiac pathophysiology. Moreover, we demonstrate that complete frataxin-deficiency neither induces oxidative stress in neuronal tissues nor alters the MnSOD expression and induction in the early step of the pathology (neuronal and cardiac) as previously suggested. We show that cytosolic ISC aconitase activity of iron regulatory protein-1 progressively decreases, whereas its apo-RNA binding form increases despite the absence of oxidative stress, suggesting that in a mammalian system the mitochondrial ISC assembly machinery is essential for cytosolic ISC biogenesis. In conclusion, our data demonstrate that in FRDA, mitochondrial iron accumulation does not induce oxidative stress and we propose that, contrary to the general assumption, FRDA is a neurodegenerative disease not associated with oxidative damage.

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  • HCP1 is abundantly expressed on the brush border of enterocytes in the duodenum, the primary location of intestinal iron absorption, and appears to mediate cellular heme uptake.

    “This protein, named heme carrier protein 1 (HCP1), is abundantly expressed on the brush border of enterocytes in the duodenum, the primary location of intestinal iron absorption, and it appears to mediate cellular heme uptake (Fig. 3).”

    From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [277]

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Authors
Seznec, H., Simon, D., Bouton, C., Reutenauer, L., Hertzog, A., Golik, P., Procaccio, V., Patel, M., Drapier, J.-C., Koenig, M., & Puccio, H.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Institut de génétique et de biologie moléculaire et cellulaire (FR)
  • Institut de Chimie des Substances Naturelles (FR)
Corresponding author
Seznec, Hervé
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2004-12-22
Volume
14
Issue
4
Pages
463-474
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddi042
OpenAlex
W2120374147
Cited by
219
References
112
Citations by year
2026: 3 · 2025: 5 · 2024: 3 · 2023: 2 · 2022: 8 · 2021: 6 · 2020: 3 · 2019: 7 · 2018: 8 · 2017: 7 · 2016: 5 · 2015: 6 · 2014: 8 · 2013: 9 · 2012: 15
FWCI
7.16
Type
journal article
Language
en
Open access
closed
Locations
  • Human Molecular Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (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 › Neuroscience › Neurology › Neurological diseases and metabolism
Keywords
Friedreich's ataxia, frataxin, oxidative stress, iron-sulfur clusters, mitochondrial iron overload, superoxide dismutase, MnTBAP, copper-zinc superoxide dismutase, iron regulatory protein 1, aconitase, cardiomyopathy, neurodegeneration, antioxidants, idebenone, heme biosynthesis
MeSH terms
Animals, Binding Sites, Cytosol, Friedreich Ataxia, Iron, Iron-Sulfur Proteins, Manganese, Metalloporphyrins, Mitochondria, Cardiomyopathies, Neurons, Oxidation-Reduction, RNA, Superoxide Dismutase, Free Radical Scavengers, Mice, Knockout, Oxidative Stress, Gene Expression Profiling, Iron Regulatory Protein 1, Microarray Analysis, Mice

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