The Friedreich's ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis
Abstract
Expansions of an intronic GAA repeat reduce the expression of frataxin and cause Friedreich's ataxia (FRDA), an autosomal recessive neurodegenerative disease. Frataxin is a mitochondrial protein, and disruption of a frataxin homolog in yeast results in increased sensitivity to oxidant stress, increased mitochondrial iron and respiration deficiency. These previous data support the hypothesis that FRDA is a disease of mitochondrial oxidative stress, a hypothesis we have tested in cultured cells from FRDA patients. FRDA fibroblasts were hypersensitive to iron stress and significantly more sensitive to hydrogen peroxide than controls. The iron chelator deferoxamine rescued FRDA fibroblasts more than controls from oxidant-induced death, consistent with a role for iron in the differential kinetics of death; however, mean mitochondrial iron content in FRDA fibroblasts was increased by only 40%. Treatment of cells with the intracellular Ca2+chelator BAPTA-AM rescued both FRDA fibroblasts and controls from oxidant-induced death. Treatment with apoptosis inhibitors rescued FRDA but not control fibroblasts from oxidant stress, and staurosporine-induced caspase 3 activity was higher in FRDA fibroblasts, consistent with the possibility that an apoptotic step upstream of caspase 3 is activated in FRDA fibroblasts. These results demonstrate that FRDA fibroblasts are sensitive to oxidant stress, and may be a useful model in which to elucidate the FRDA mechanism and therapeutic strategies.
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Chemicals used to model PD, such as MPTP, 6-OHDA, and rotenone, increase expression of key members of the signaling pathway associated with the UPR in ER stress.
“It may be noted that chemicals used to model PD, such as MPTP, 6-hydroxydopamine (6-OHDA), and rotenone, were shown to increase expression of key members of the signaling pathway associated with the UPR in ER stress (136, 327).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [327]
Cites
Induction of Apoptotic Program in Cell-Free Extracts: Requirement for dATP and Cytochrome c
Liu, X., Kim, C. N., Yang, J., Jemmerson, R., & Wang, X. (1996) · Cell · doi:10.1016/s0092-8674(00)80085-9 · Cited by 5,167 · see citing works
Prevention of Apoptosis by Bcl-2: Release of Cytochrome c from Mitochondria Blocked
Yang, J., Liu, X., Bhalla, K. N., Kim, C. N., Ibrado, A. M., Cai, J., Peng, T.-I., Jones, D. P., & Wang, X. (1997) · Science · doi:10.1126/science.275.5303.1129 · Cited by 4,913 · see citing works
The Release of Cytochrome c from Mitochondria: A Primary Site for Bcl-2 Regulation of Apoptosis
Kluck, R. M., Bossy‐Wetzel, E., Green, D. R., & Newmeyer, D. D. (1997) · Science · doi:10.1126/science.275.5303.1132 · Cited by 4,715 · 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
Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation
(1990) · Trends in Genetics · doi:10.1016/0168-9525(90)90040-d · Cited by 1,386 · 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
Regulation 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
Newmeyer, D. (1994) · Cell · doi:10.1016/0092-8674(94)90203-8 · Cited by 581 · see citing works
Filla, A., Michele, G. D., Cavalcanti, F., Pianese, L., Monticelli, A., Campanella, G., & Cocozza, S. (1996) · PubMed Central · Cited by 487 · see citing works
Clinical features and classification of inherited ataxias.
Harding, A. E. B. (1993) · PubMed · Cited by 423 · see citing works
Mitochondria, free radicals, and neurodegeneration
Beal, M. F. (1996) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(96)80100-0 · Cited by 422 · see citing works
Mitochondria: a practical approach.
Darley-Usmar, V. M., RICKWOOD, D., & Wilson, M. T. (1987) · IRL Press eBooks · Cited by 410 · see citing works
Foury, F., & Cazzalini, O. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)00734-5 · Cited by 378 · see citing works
Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue
Wilson, R. B., & Roof, D. M. (1997) · Nature Genetics · doi:10.1038/ng0897-352 · Cited by 345 · see citing works
Ohshima, K., Montermini, L., Wells, R. D., & Pandolfo, M. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.23.14588 · Cited by 302 · see citing works
Yang, J. C., & Cortopassi, G. A. (1998) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(97)00367-5 · Cited by 219 · see citing works
Fransson, G.-B., & Lönnerdal, B. (1980) · The Journal of Pediatrics · doi:10.1016/s0022-3476(80)80676-7 · Cited by 204 · see citing works
Verderio, E. A. M., Cavadini, P., Montermini, L., Wang, H., Lamantea, E., Finocchiaro, G., DiDonato, S., Gellera, C., & Taroni, F. (1995) · Human Molecular Genetics · doi:10.1093/hmg/4.1.19 · Cited by 94 · see citing works
Wong, A., & Cortopassi, G. A. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.7443 · Cited by 86 · see citing works
Self-citationAn established avian fibroblast cell line without mitochondrial DNA
Desjardins, P., de Muys, J.-M., & Morais, R. (1986) · Somatic Cell and Molecular Genetics · doi:10.1007/bf01560660 · Cited by 70 · see citing works
Mattson, M. P. (1996) · PubMed · Cited by 67 · see citing works
Ouvrier, R., McLeod, J. G., & Conchin, T. E. (1982) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(82)90095-8 · Cited by 67 · see citing works
Iron-Chelating Agents in Non-Iron Overload Conditions
Voest, E. E., Vreugdenhil, G., & Marx, J. J. M. (1994) · Annals of Internal Medicine · doi:10.7326/0003-4819-120-6-199403150-00008 · Cited by 63 · see citing works
Mechanisms of calcium-related cell death.
Orrenius, S., Ankarcrona, M., & Nicotera, P. (1996) · PubMed · Cited by 56 · see citing works
Gellera, C., Pareyson, D., Castellotti, B., et al. (1997) · Neurology · doi:10.1212/wnl.49.4.1153 · Cited by 38 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Neurodegenerative diseases and oxidative stress
Barnham, K. J., Masters, C. L., & Bush, A. I. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1330 · Cited by 3,683 · 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
Kell, D. B. (2009) · BMC Medical Genomics · doi:10.1186/1755-8794-2-2 · Cited by 554 · 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
Selective iron chelation in Friedreich ataxia: biologic and clinical implications
Boddaert, N., Le Quan Sang, K. H., Rötig, A., Leroy-Willig, A., Gallet, S., Brunelle, F., Sidi, D., Thalabard, J.-C., Munnich, A., & Cabantchik, Z. I. (2007) · Blood · doi:10.1182/blood-2006-12-065433 · Cited by 409 · see citing works
Scott, L. E., & Orvig, C. (2009) · Chemical Reviews · doi:10.1021/cr9000176 · Cited by 332 · 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
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
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
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
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
Campanella, A., Rovelli, E., Santambrogio, P., Cozzi, A., Taroni, F., & Levi, S. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn308 · Cited by 162 · 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
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
Friedreich 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
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
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
Iron, oxidative stress and the example of solar ultraviolet a radiation.
Aroun, A., Zhong, J. L., Tyrrell, R. M., & Pourzand, C. (2012) · Photochemical & Photobiological Sciences · doi:10.1039/c1pp05204g · Cited by 74 · see citing works
Frataxin: its role in iron metabolism and the pathogenesis of Friedreich's ataxia
Becker, E., & Richardson, D. R. (2001) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(00)00067-4 · Cited by 71 · see citing works
Deferiprone targets aconitase: Implication for Friedreich's ataxia treatment
Goncalves, S., Paupe, V., Dassa, E. P., & Rustin, P. (2008) · BMC Neurology · doi:10.1186/1471-2377-8-20 · Cited by 66 · see citing works
Open-minded scepticism: inferring the causal mechanisms of human ageing from genetic perturbations
de Magalhães, J. P. (2005) · Ageing Research Reviews · doi:10.1016/j.arr.2004.05.003 · Cited by 54 · see citing works
The chemical form of mitochondrial iron in Friedreich’s ataxia
Popescu, B. F. G., Pickering, I. J., George, G. N., & Nichol, H. (2007) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2007.03.004 · Cited by 36 · see citing works
Frataxin 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
Miranda, C. J., Santos, M. M., Ohshima, K., Tessaro, M., Sequeiros, J., & Pandolfo, M. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.07.022 · Cited by 30 · see citing works
- Authors
- Wong, A.
- Affiliations
- University of California, Davis (US)
- Corresponding author
- Wong, A
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 1999-03-01
- Volume
- 8
- Issue
- 3
- Pages
- 425-430
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2145136975
- Cited by
- 374
- References
- 26
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 7 · 2023: 8 · 2022: 9 · 2021: 7 · 2020: 16 · 2019: 14 · 2018: 12 · 2017: 9 · 2016: 9 · 2015: 12 · 2014: 19 · 2013: 20 · 2012: 11
- FWCI
- 8.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG-11967, R01AG011967)
- 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, GAA repeat expansion, intronic repeat expansion, mitochondrial oxidative stress, oxidative stress, hydrogen peroxide sensitivity, iron chelation, deferoxamine, calcium chelation, BAPTA-AM, apoptosis, caspase-3, mitochondrial iron, fibroblasts, neurodegeneration
- MeSH terms
- Frataxin, Base Sequence, Calcium, Cell Line, Chelating Agents, Deferoxamine, Egtazic Acid, Fibroblasts, Friedreich Ataxia, Humans, Hydrogen Peroxide, Iron, Mutation, RNA, Messenger, Uridine, Case-Control Studies, Apoptosis, Phosphotransferases (Alcohol Group Acceptor), DNA Primers, Oxidative Stress, Pyruvic Acid, Caspases, Iron-Binding Proteins, Caspase 3
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