Idebenone delays the onset of cardiac functional alteration without correction of Fe-S enzymes deficit in a mouse model for Friedreich ataxia
Abstract
Friedreich ataxia (FRDA), a progressive neurodegenerative disorder associated with cardiomyopathy, is caused by severely reduced frataxin, a mitochondrial protein involved in Fe-S cluster assembly. We have recently generated mouse models that reproduce important progressive pathological and biochemical features of the human disease. Our frataxin-deficient mouse models initially demonstrate time-dependent intramitochondrial iron accumulation, which occurs after onset of the pathology and after inactivation of the Fe-S dependent enzymes. Here, we report a more detailed pathophysiological characterization of our mouse model with isolated cardiac disease by echocardiographic, biochemical and histological studies and its use for placebo-controlled therapeutic trial with Idebenone. The Fe-S enzyme deficiency occurs at 4 weeks of age, prior to cardiac dilatation and concomitant development of left ventricular hypertrophy, while the mitochondrial iron accumulation occurs at a terminal stage. From 7 weeks onward, Fe-S enzyme activities are strongly decreased and are associated with lower levels of oxidative stress markers, as a consequence of reduced respiratory chain activity. Furthermore, we demonstrate that the antioxidant Idebenone delays the cardiac disease onset, progression and death of frataxin deficient animals by 1 week, but does not correct the Fe-S enzyme deficiency. Our results support the view that frataxin is a necessary, albeit non-essential, component of the Fe-S cluster biogenesis, and indicate that Idebenone acts downstream of the primary Fe-S enzyme deficit. Furthermore, our results demonstrate that Idebenone is cardioprotective even in the context of a complete lack of frataxin, which further supports its utilization for the treatment of FRDA.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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 contrast to wild-type HFE2, the mutant HFE2 isoforms were not regulated by iron levels.
“In addition, in contrast to wild-type HFE2, the mutant isoforms were not regulated by iron levels.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [278]
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 · see citing works
Biochemical and molecular investigations in respiratory chain deficiencies
Rustin, P., Chrétien, D., Bourgeron, T., Gérard, B., Rötig, A., Saudubray, J., & Münnich, A. (1994) · Clinica Chimica Acta · doi:10.1016/0009-8981(94)90055-8 · Cited by 1,239 · see citing works
Aconitase and mitochondrial iron–sulphur protein deficiency in Friedreich ataxia
Rötig, A., de Lonlay, P., Chretien, D., Foury, F., Koenig, M., Sidi, D., Munnich, A., & Rustin, P. (1997) · Nature Genetics · doi:10.1038/ng1097-215 · Cited by 991 · see citing works
Puccio, H., Simon, D., Cossée, M., Criqui-Filipe, P., Tiziano, F., Melki, J., Hindelang, C., Matyas, R., Rustin, P., & Koenig, M. (2001) · Nature Genetics · doi:10.1038/84818 · Cited by 738 · see citing works
Intramuscular lipid content is increased in obesity and decreased by weight loss
Goodpaster, B. H., Theriault, R., Watkins, S. C., & Kelley, D. E. (2000) · Metabolism · doi:10.1016/s0026-0495(00)80010-4 · Cited by 526 · see citing works
Clinical Description and Roentgenologic Evaluation of Patients with Friedreich's Ataxia
Geoffroy, G., Barbeau, A., Breton, G., Lemieux, B., Aubé, M., Leger, C., & Bouchard, J. (1976) · Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques · doi:10.1017/s0317167100025464 · Cited by 379 · see citing works
Cossee, M. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.8.1219 · Cited by 377 · see citing works
Echocardiographic assessment of cardiac function in conscious and anesthetized mice
Yang, X.-P., Liu, Y.-H., Rhaleb, N., Kurihara, N., Kim, H. E., & Carretero, O. A. (1999) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1999.277.5.h1967 · Cited by 365 · see citing works
Effect of idebenone on cardiomyopathy in Friedreich's ataxia: a preliminary study
Rustin, P., von Kleist-Retzow, J., Chantrel-Groussard, K., Sidi, D., Münnich, A., & Rötig, A. (1999) · The Lancet · doi:10.1016/s0140-6736(99)01341-0 · Cited by 348 · see citing works
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 · see citing works
Oxidative stress in patients with Friedreich ataxia
Schulz, J. B., Dehmer, T., Schöls, L. J., Mende, H. E., Hardt, C., Vorgerd, M., Bürk, K., Matson, W. R., DICHGANS, J., Beal, M. F., et al. (2000) · Neurology · doi:10.1212/wnl.55.11.1719 · Cited by 305 · see citing works
Genetic instabilities and hereditary neurological diseases
Wells, R. D., Warren, S. T., & Sarmiento, M. (1998) · Cited by 270 · see citing works
Idebenone and reduced cardiac hypertrophy in Friedreich's ataxia
HAUSSE, A., Aggoun, Y., Bonnet, D., Sidi, D., Münnich, A., Rötig, A., & Rustin, P. (2002) · Heart · doi:10.1136/heart.87.4.346 · Cited by 251 · see citing works
Idebenone treatment in Friedreich patients: One-year-long randomized placebo-controlled trial
Mariotti, C., Solari, A., Torta, D., Marano, L., Fiorentini, C., & Donato, S. D. (2003) · Neurology · doi:10.1212/01.wnl.0000055872.50364.fc · Cited by 235 · see citing works
Echocardiographic Assessment of Left Ventricular Mass and Systolic Function in Mice
Gardin, J. M., Siri, F. M., Kitsis, R. N., Edwards, J. G., & Leinwand, L. A. (1995) · Circulation Research · doi:10.1161/01.res.76.5.907 · Cited by 220 · see citing works
Disabled early recruitment of antioxidant defenses in Friedreich's ataxia
Chantrel-Groussard, K. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.19.2061 · Cited by 189 · see citing works
Increased levels of plasma malondialdehyde in Friedreich ataxia
Emond, M., Lepage, G., Vanasse, M., & Pandolfo, M. (2000) · Neurology · doi:10.1212/wnl.55.11.1752 · Cited by 174 · see citing works
Miranda, C. J., Santos, M. M., Ohshima, K., Smith, J., Li, L., Bunting, M., Cossée, M., Koenig, M., Sequeiros, J., Kaplan, J., et al. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)02251-2 · Cited by 172 · see citing works
Chen, O. S., Hemenway, S., & Kaplan, J. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.192449599 · Cited by 152 · see citing works
In vivo assessment of LV mass in mice using high-frequency cardiac ultrasound: necropsy validation
Manning, W. J., Wei, J. Y., Katz, S. E., Litwin, S. E., & Douglas, P. S. (1994) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1994.266.4.h1672 · Cited by 140 · see citing works
Handbook of cerebellar diseases
Lechtenberg, R. J. (1993) · M. Dekker eBooks · Cited by 128 · see citing works
A non-essential function for yeast frataxin in iron-sulfur cluster assembly
Duby, G. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.21.2635 · Cited by 117 · see citing works
Antioxidant Properties of 2,3-Dimethoxy-5-methyl- 6-(10-hydroxydecyl)-1,4-benzoquinone (Idebenone)
Mordente, A., Martorana, G. E., Minotti, G., & Giardina, B. (1998) · Chemical Research in Toxicology · doi:10.1021/tx970136j · Cited by 114 · see citing works
Friedreich's Ataxia: Idebenone Treatment in Early Stage Patients
Artuch, R., Aracil, A., Mas, A., Colomé, C., Rissech, M., Monrós, E., & Pineda, M. (2002) · Neuropediatrics · doi:10.1055/s-2002-34494 · Cited by 112 · see citing works
Friedreich ataxia: a paradigm for mitochondrial diseases
Puccio, H. M., & Koenig, M. (2002) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(02)00298-8 · Cited by 111 · see citing works
Gillis, J. C., Benfield, P., & McTavish, D. (1994) · Drugs & Aging · doi:10.2165/00002512-199405020-00007 · Cited by 104 · see citing works
Idebenone in patients with Friedreich ataxia
Schöls, L. J., Vorgerd, M., Schillings, M., Skipka, G., & Zange, J. (2001) · Neuroscience Letters · doi:10.1016/s0304-3940(01)01892-4 · Cited by 89 · see citing works
Frataxin expression rescues mitochondrial dysfunctions in FRDA cells
Tan, G. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.19.2099 · Cited by 82 · see citing works
Cardiac Aspects of Friedreich's Ataxia
Boyer, S. H., CHISHOLM, A. W., & McKusick, V. A. (1962) · Circulation · doi:10.1161/01.cir.25.3.493 · Cited by 79 · see citing works
The heart in Friedreich's ataxia.
Pentland, B., & Fox, K. A. A. (1983) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.46.12.1138 · Cited by 38 · see citing works
Idebenone treatment in Friedreich patients: One-year-long randomized placebo-controlled trial
Rustin, P., Bonnet, D., Rötig, A., Münnich, A., & Sidi, D. (2004) · Neurology · doi:10.1212/wnl.62.3.524 · Cited by 35 · see citing works
Pandolfo, M. (2006) · Elsevier eBooks · doi:10.1016/b978-012369462-1/50018-1 · Cited by 31 · see citing works
Friedreich's Ataxia: Cardiac Evaluation of 25 Patients with Clinical Diagnosis and Literature Review
Albano, L. M. J., Nishioka, S., Moysés, R. L., et al. (2002) · Arquivos Brasileiros de Cardiologia · doi:10.1590/s0066-782x2002000500002 · Cited by 21 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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 · see citing works
Friedreich ataxia: the oxidative stress paradox
Seznec, H., Simon, D., Bouton, C., Reutenauer, L., Hertzog, A., Golik, P., Procaccio, V., Patel, M., Drapier, J.-C., Koenig, M., et al. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi042 · Cited by 219 · see citing works
Self-citationGakh, O., Park, S., Liu, G., Macomber, L., Imlay, J. A., Ferreira, G. C., & Isaya, G. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddi461 · Cited by 184 · see citing works
Iron: A New Target for Pharmacological Intervention in Neurodegenerative Diseases
Whitnall, M., & Richardson, D. R. (2006) · Seminars in Pediatric Neurology · doi:10.1016/j.spen.2006.08.008 · Cited by 113 · see citing works
Lu, C., & Cortopassi, G. (2007) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2006.09.010 · Cited by 94 · see citing works
Grant, L., Sun, J., Xu, H., Subramony, S. H., Chaires, J. B., & Hebert, M. D. (2006) · FEBS Letters · doi:10.1016/j.febslet.2006.09.006 · Cited by 36 · see citing works
- Authors
- Seznec, H.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Seznec, H.
- ORCID
- Seznec, H.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-03-17
- Volume
- 13
- Issue
- 10
- Pages
- 1017-1024
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2124756854
- Cited by
- 138
- References
- 34
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 5 · 2018: 6 · 2017: 2 · 2016: 2 · 2015: 5 · 2014: 7 · 2013: 9 · 2012: 7
- FWCI
- 5.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HAL (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 › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- Friedreich's ataxia, idebenone, frataxin deficiency, iron-sulfur cluster assembly, mitochondrial iron accumulation, cardiomyopathy, left ventricular hypertrophy, oxidative stress, respiratory chain activity, cardioprotection
- MeSH terms
- Frataxin, Animals, Cardiomyopathy, Dilated, Disease Models, Animal, Electrocardiography, Friedreich Ataxia, Iron-Sulfur Proteins, Mitochondria, Myocardium, Ubiquinone, Benzoquinones, Oxidative Stress, Iron-Binding Proteins, Mice
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
