Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits
Abstract
Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy and increased incidence in diabetes. FRDA is caused by severely reduced levels of frataxin, a mitochondrial protein of unknown function. Yeast knockout models as well as histological and biochemical data from heart biopsies or autopsies of FRDA patients have shown that frataxin defects cause a specific iron-sulfur protein deficiency and intramitochondrial iron accumulation. We have recently shown that complete absence of frataxin in the mouse leads to early embryonic lethality, demonstrating an important role for frataxin during mouse development. Through a conditional gene-targeting approach, we have generated in parallel a striated muscle frataxin-deficient line and a neuron/cardiac muscle frataxin-deficient line, which together reproduce important progressive pathophysiological and biochemical features of the human disease: cardiac hypertrophy without skeletal muscle involvement, large sensory neuron dysfunction without alteration of the small sensory and motor neurons, and deficient activities of complexes I-III of the respiratory chain and of the aconitases. Our models demonstrate time-dependent intramitochondrial iron accumulation in a frataxin-deficient mammal, which occurs after onset of the pathology and after inactivation of the Fe-S-dependent enzymes. These mutant mice represent the first mammalian models to evaluate treatment strategies for the human disease.
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Proteasome-mediated ferritin degradation has been reported.
“Proteasome-mediated ferritin degradation has also been reported (199, 255).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [255]
Cites
Molecular Cloning: A Laboratory Manual
Sambrook, J., Fritsch, E., & Maniatis, T. (1989) · UCLA - Biblioteca de Ciencias de la Salud · Cited by 133,589 · see citing works
Molecular cloning: A laboratory manual
Deininger, P. L. (1990) · Analytical Biochemistry · doi:10.1016/0003-2697(90)90595-z · Cited by 84,684 · see citing works
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
Self-citationBiochemical 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
Self-citationClinical and Genetic Abnormalities in Patients with Friedreich's Ataxia
Dürr, A., Cossee, M., Agid, Y., Campuzano, V., Mignard, C., Penet, C., Mandel, J.-L., Brice, A., & Koenig, M. (1996) · New England Journal of Medicine · doi:10.1056/nejm199610173351601 · Cited by 1,071 · see citing works
Self-citationAconitase 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
Self-citationRegulation of Mitochondrial Iron Accumulation by Yfh1p, a Putative Homolog of Frataxin
Babcock, M., de Silva, D., Oaks, R., Davis-Kaplan, S., Jiralerspong, S., Montermini, L., Pandolfo, M., & Kaplan, J. (1997) · Science · doi:10.1126/science.276.5319.1709 · Cited by 921 · see citing works
Frataxin is Reduced in Friedreich Ataxia Patients and is Associated with Mitochondrial Membranes
Campuzano, V., Montermini, L., Lutz, Y., Cova, L., Hindelang, C., Jiralerspong, S., Trottier, Y., Kish, S. J., Faucheux, B. A., Trouillas, P., et al. (1997) · Human Molecular Genetics · doi:10.1093/hmg/6.11.1771 · Cited by 739 · see citing works
Self-citationStudies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin
Koutníková, H., Campuzano, V., Foury, F., Dollé, P., Cazzalini, O., & Koenig, M. (1997) · Nature Genetics · doi:10.1038/ng0897-345 · Cited by 473 · see citing works
Self-citationWang, J., Wilhelmsson, H., Graff, C., Li, H., Oldfors, A., Rustin, P., Brüning, J. C., Kahn, C. R., Clayton, D. A., Barsh, G. S., et al. (1999) · Nature Genetics · doi:10.1038/5089 · Cited by 435 · see citing works
Self-citationFoury, F., & Cazzalini, O. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)00734-5 · Cited by 378 · see citing works
Cossee, M. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.8.1219 · Cited by 377 · see citing works
In vivo functional analysis of the Hoxa-1 3′ retinoic acid response element (3′ RARE)
Dupé, V., Davenne, M., Brocard, J., Dollé, P., Mark, M. P., Dierich, A., Chambon, P., & Rijli, F. M. (1997) · Development · doi:10.1242/dev.124.2.399 · Cited by 335 · see citing works
The Yeast Frataxin Homologue Mediates Mitochondrial Iron Efflux
Radisky, D. C., Babcock, M. C., & Kaplan, J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.8.4497 · Cited by 277 · see citing works
Nuclear targeting defect of SMN lacking the C-terminus in a mouse model of spinal muscular atrophy
Frugier, T. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.5.849 · Cited by 259 · see citing works
Iron-Dependent Self-Assembly of Recombinant Yeast Frataxin: Implications for Friedreich Ataxia
Adamec, J., Rusnak, F., Owen, W. G., Naylor, S., Benson, L. M., Gacy, A. M., & Isaya, G. (2000) · The American Journal of Human Genetics · doi:10.1086/303056 · Cited by 255 · see citing works
Crystal Structure of Human Frataxin
Dhe-Paganon, S., Shigeta, R., Chi, Y.-I., Ristow, M., & Shoelson, S. E. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.c000407200 · Cited by 226 · see citing works
Cardiovascular phenotyping in mice.
Doevendans, P., Daemen, M., de Muinck, E. D., & Smits, J. (1998) · Cardiovascular Research · doi:10.1016/s0008-6363(98)00073-x · Cited by 201 · see citing works
Towards a structural understanding of Friedreich’s ataxia: the solution structure of frataxin
Musco, G., Stier, G., Kolmerer, B., Adinolfi, S., Martin, S., Frenkiel, T., Gibson, T., & Pastore, A. (2000) · Structure · doi:10.1016/s0969-2126(00)00158-1 · Cited by 166 · see citing works
NEUROMYOPATHY AND VITAMIN E DEFICIENCY in MAN1
Burck, U., Goebel, H. H., Kuhlendahl, H., Meier, C., & Goebel, K. M. (1981) · Neuropediatrics · doi:10.1055/s-2008-1059657 · Cited by 146 · see citing works
Low iron concentration and aconitase deficiency in a yeast frataxin homologue deficient strain
Foury, F. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00961-8 · Cited by 145 · see citing works
Handbook of cerebellar diseases
Lechtenberg, R. J. (1993) · M. Dekker eBooks · Cited by 126 · see citing works
Watmough, N. J., Bindoff, L. A., Birch‐Machin, M. A., Jackson, S., Bartlett, K., RAGAN, C. I., Poulton, J., Gardiner, R. M., Sherratt, H. S. A., & Turnbull, D. M. (1990) · Journal of Clinical Investigation · doi:10.1172/jci114409 · Cited by 77 · see citing works
Frataxin Shows Developmentally Regulated Tissue-Specific Expression in the Mouse Embryo
Jiralerspong, S., Liu, Y., Montermini, L., Stifani, S., & Pandolfo, M. (1997) · Neurobiology of Disease · doi:10.1006/nbdi.1997.0139 · Cited by 76 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Chemistry and biology of eukaryotic iron metabolism
Aisen, P. (2001) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(01)00063-2 · Cited by 804 · see citing works
Iron Homeostasis and Ferroptosis in Human Diseases: Mechanisms and Therapeutic Prospects
Ru, Q., Li, Y., Chen, L., Wu, Y., Min, J., & Wang, F. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01969-z · Cited by 724 · see citing works
The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer
Kalinowski, D. S., & Richardson, D. R. (2005) · Pharmacological Reviews · doi:10.1124/pr.57.4.2 · Cited by 721 · see citing works
Richardson, D. R., Lane, D. J. R., Becker, E. M., Huang, M. L.-H., Whitnall, M., Rahmanto, Y. S., Sheftel, A. D., & Ponka, P. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912925107 · Cited by 536 · see citing works
Copper and iron disorders of the brain
Madsen, E., & Gitlin, J. D. (2007) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.30.051606.094232 · Cited by 557 · see citing works
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
Conrad, M., Jakupoglu, C., Moreno, S. G., Lippl, S., Banjac, A., Schneider, M., Beck, H., Hatzopoulos, A. K., Just, U., Sinowatz, F., et al. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.21.9414-9423.2004 · Cited by 485 · see citing works
Friedreich's ataxia: Pathology, pathogenesis, and molecular genetics
Koeppen, A. H. (2011) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2011.01.010 · Cited by 447 · see citing works
Lane, D. J. R., Merlot, A. M., Huang, M. L.-H., Bae, D.-H., Jansson, P. J., Sahni, S., Kalinowski, D. S., & Richardson, D. R. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.01.021 · Cited by 399 · see citing works
Iron Toxicity in Diseases of Aging: Alzheimer's Disease, Parkinson's Disease and Atherosclerosis
Altamura, S., & Muckenthaler, M. U. (2009) · Journal of Alzheimer's Disease · doi:10.3233/jad-2009-1010 · Cited by 369 · see citing works
Iron-Sulfur Protein Biogenesis in Eukaryotes: Components and Mechanisms
Lill, R., & Mühlenhoff, U. (2006) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.22.010305.104538 · Cited by 365 · see citing works
Jauslin, M. L., Meier, T., Smith, R. A. J., & Murphy, P. M. (2003) · The FASEB Journal · doi:10.1096/fj.03-0240fje · Cited by 358 · see citing works
Anderson, G. J., & Vulpe, C. D. (2009) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-009-0051-1 · Cited by 317 · see citing works
Mitochondria, oxygen free radicals, and apoptosis
Raha, S., & Robinson, B. H. (2001) · American Journal of Medical Genetics · doi:10.1002/ajmg.1398 · Cited by 306 · see citing works
Iron use for haeme synthesis is under control of the yeast frataxin homologue (Yfh1)
Lesuisse, E. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg096 · Cited by 226 · 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-citationHuang, M. L.-H., Becker, E. M., Whitnall, M., Rahmanto, Y. S., Ponka, P., & Richardson, D. R. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906784106 · Cited by 212 · see citing works
Simon, D., Seznec, H., Gansmuller, A., Carelle, N., Weber, P., Metzger, D., Rustin, P., Koenig, M., & Puccio, H. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.4549-03.2004 · Cited by 205 · see citing works
Self-citationIron-starvation-induced mitophagy mediates lifespan extension upon mitochondrial stress in C.elegans
Schiavi, A., Maglioni, S., Palikaras, K., Shaik, A., Strappazzon, F., Brinkmann, V., Torgovnick, A., Castelein, N., De Henau, S., Braeckman, B. P., et al. (2015) · Current Biology · doi:10.1016/j.cub.2015.05.059 · Cited by 209 · see citing works
The role of mitochondria in inherited neurodegenerative diseases
Kwong, J. Q., Beal, M. F., & Manfredi, G. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03990.x · Cited by 180 · see citing works
Iron–sulfur protein maturation in human cells: evidence for a function of frataxin
Stehling, O., Elsässer, H.-P., Brückel, B., Mühlenhoff, U., & Lill, R. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh324 · Cited by 176 · 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
Self-citationFoury, F., & Roganti, T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111789200 · Cited by 171 · see citing works
Colin, F., Martelli, A., Clémancey, M., Latour, J.-M., Gambarelli, S., Zeppieri, L., Birck, C., Page, A., Puccio, H., & Ollagnier de Choudens, S. (2013) · Journal of the American Chemical Society · doi:10.1021/ja308736e · Cited by 148 · see citing works
Self-citationRNAi-mediated suppression of the mitochondrial iron chaperone, frataxin, in Drosophila
Anderson, P. R., Kirby, K., Hilliker, A. J., & Phillips, J. P. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi367 · Cited by 144 · see citing works
Metal Acquisition and Availability in the Mitochondria
Atkinson, A., & Winge, D. R. (2009) · Chemical Reviews · doi:10.1021/cr900006y · Cited by 146 · see citing works
Frataxin interacts functionally with mitochondrial electron transport chain proteins
González-Cabo, P., Vázquez-Manrique, R. P., García-Gimeno, M. A., Sanz, P., & Palau, F. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi214 · Cited by 140 · see citing works
Nabhan, J. F., Wood, K. M., Rao, V. P., Morin, J., Bhamidipaty, S., LaBranche, T. P., Gooch, R. L., Bozal, F., Bulawa, C. E., & Guild, B. C. (2016) · Scientific Reports · doi:10.1038/srep20019 · Cited by 140 · see citing works
Seznec, H. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh114 · Cited by 138 · see citing works
Martin, A. S., Abraham, D. M., Hershberger, K. A., Bhatt, D. P., Mao, L., Cui, H., Liu, J., Liu, X., Muehlbauer, M. J., Grimsrud, P. A., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.93885 · Cited by 128 · see citing works
Thierbach, R., Schulz, T. J., Isken, F., Voigt, A., Mietzner, B., Drewes, G., von Kleist-Retzow, J.-C., Wiesner, R. J., Magnuson, M. A., Puccio, H., et al. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi410 · Cited by 127 · see citing works
Self-citationFriedreich Ataxia: From GAA Triplet–Repeat Expansion to Frataxin Deficiency
Patel, P. I., & Isaya, G. (2001) · The American Journal of Human Genetics · doi:10.1086/321283 · Cited by 126 · see citing works
In vivo maturation of human frataxin
Condò, I., Ventura, N., Malisan, F., Rufini, A., Tomassini, B., & Testi, R. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm102 · Cited by 118 · 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
Campanella, A. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh232 · Cited by 109 · see citing works
Does oxidative stress contribute to the pathology of Friedreich's ataxia? A radical question
Armstrong, J. S., Khdour, O., & Hecht, S. M. (2010) · The FASEB Journal · doi:10.1096/fj.09-143222 · Cited by 107 · see citing works
Anderson, P. R., Kirby, K., Orr, W. C., Hilliker, A. J., & Phillips, J. P. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709691105 · Cited by 105 · see citing works
Mitochondrial Mayhem: The Mitochondrion as a Modulator of Iron Metabolism and Its Role in Disease
Huang, M. L.-H., Lane, D. J. R., & Richardson, D. R. (2011) · Antioxidants & Redox Signaling · doi:10.1089/ars.2011.3921 · Cited by 103 · 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
Compartmentalization of iron between mitochondria and the cytosol and its regulation
Mühlenhoff, U., Hoffmann, B., Richter, N., Rietzschel, N., Spantgar, F., Stehling, O., Uzarska, M. A., & Lill, R. (2015) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2015.05.003 · Cited by 95 · see citing works
The Ferroxidase Activity of Yeast Frataxin
Park, S., Gakh, O., Mooney, S. M., & Isaya, G. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206711200 · Cited by 88 · see citing works
Cytopathies involving mitochondrial complex II
Ackrell, B. A. C. (2002) · Molecular Aspects of Medicine · doi:10.1016/s0098-2997(02)00012-2 · Cited by 86 · 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
Advancements in the pathophysiology of Friedreich’s Ataxia and new prospects for treatments
Babady, N. E., Carelle, N., Wells, R. D., Rouault, T. A., Hirano, M., Lynch, D. R., Delatycki, M. B., Wilson, R. B., Isaya, G., & Puccio, H. (2007) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2007.05.009 · Cited by 73 · see citing works
Self-citationFriedreich's Ataxia, No Changes in Mitochondrial Labile Iron in Human Lymphoblasts and Fibroblasts
Sturm, B., Bistrich, U., Schranzhofer, M., Sarsero, J. P., Rauen, U., Scheiber-Mojdehkar, B., de Groot, H., Ioannou, P., & Petrat, F. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m408717200 · Cited by 73 · see citing works
Santos, R., Buisson, N., Knight, S. A. B., Dancis, A., Camadro, J., & Lesuisse, E. (2004) · Molecular Microbiology · doi:10.1111/j.1365-2958.2004.04281.x · Cited by 55 · see citing works
Molecular insights into Friedreich's ataxia and antioxidant-based therapies
Rötig, A., Sidi, D., Munnich, A., & Rustin, P. (2002) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(02)02330-4 · Cited by 46 · see citing works
Self-citationFrataxin and frataxin deficiency in Friedreich's ataxia
Wilson, R. B. (2003) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(02)00432-x · Cited by 32 · see citing works
Wong, A. O.-T., Wong, G., Shen, M., Chow, M. Z.-Y., Tse, W. W., Gurung, B., Mak, S. Y., Lieu, D. K., Costa, K. D., Chan, C. W., et al. (2019) · Stem Cell Research & Therapy · doi:10.1186/s13287-019-1305-y · Cited by 27 · see citing works
- Authors
- Puccio, H., Simon, D., Cossée, M., Criqui-Filipe, P., Tiziano, F., Melki, J., Hindelang, C., Matyas, R., Rustin, P., & Koenig, M.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Corresponding author
- Koenig, Michel
- Venue
- Nature Genetics
- Published
- 2001-02
- Volume
- 27
- Issue
- 2
- Pages
- 181-186
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1484379620
- Cited by
- 738
- References
- 25
- Citations by year
- 2026: 19 · 2025: 18 · 2024: 28 · 2023: 17 · 2022: 24 · 2021: 20 · 2020: 30 · 2019: 21 · 2018: 24 · 2017: 20 · 2016: 25 · 2015: 24 · 2014: 33 · 2013: 43 · 2012: 34
- FWCI
- 16.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature 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, mouse model, cardiomyopathy, cardiac hypertrophy, sensory neuron degeneration, iron-sulfur proteins, conditional gene targeting, embryonic lethality, mitochondrial iron
- MeSH terms
- Frataxin, Animals, Friedreich Ataxia, Iron-Sulfur Proteins, Mice, Mutant Strains, Mitochondria, Cardiomyopathies, Hereditary Sensory and Autonomic Neuropathies, Mutagenesis, Phosphotransferases (Alcohol Group Acceptor), Gene Targeting, Iron-Binding Proteins, Mice
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