The expression of human mitochondrial ferritin rescues respiratory function infrataxin-deficient yeast
Abstract
Mitochondrial ferritin (MtF) is structurally and functionally similar to the cytosolic ferritins, molecules designed to store and detoxify cellular iron. MtF expression in human and mouse is restricted to the testis and few tissues, and it is abundant in the erythroblasts of patients with sideroblastic anemia, where it is thought to protect the mitochondria from the damage caused by iron loading. Mitochondria iron overload occurs also in cells deficient in frataxin, a mitochondrial protein involved in iron handling and implicated in Friedreich ataxia. We expressed human MtF in frataxin-deficient yeast cells, a well-characterized model of mitochondrial iron overload and oxidative damage. The human MtF precursor was efficiently imported by yeast mitochondria and processed to functional ferritin that actively sequestered iron in the organelle. MtF expression rescued the respiratory deficiency caused by the loss of frataxin protecting the activity of iron-sulfur enzymes and enabling frataxin-deficient cells to grow on non-fermentable carbon sources. Furthermore, MtF expression prevented the development of mitochondrial iron overload, preserved mitochondrial DNA integrity and increased cell resistance to H2O2. The data show that MtF can substitute for most frataxin functions in yeast, suggesting that frataxin is directly involved in mitochondrial iron-binding and detoxification.
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FRDA is most commonly (96% to 98%) caused by homozygous hyperexpansion of a GAA trinucleotide repeat in the first intron of the frataxin gene, which results in marked repression of frataxin transcription.
“FRDA is most commonly (96% to 98%) caused by the homozygous hyperexpansion of a GAA trinucleotide repeat in the first intron of the frataxin gene, which results in a marked repression of frataxin transcription (37).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [37]
The GAA repeat in FRDA patients ranges from 100 to >1,000 repeats, whereas normal individuals have fewer than 35 repeats.
“The GAA repeat in FRDA patients ranges from 100 to >1,000 repeats, whereas normal individuals have fewer than 35 repeats (37).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [37]
The human frataxin gene is located on chromosome 9 (q13-q21.1) and consists of seven exons spanning >95 kb of genomic DNA.
“The human frataxin gene is located on chromosome 9 (q13-q21.1) consisting of seven exons spanning >95 kb of the genomic DNA (37).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [37]
The most abundant frataxin mRNA is a transcript from exon 1 to exon 5a, with a size of 1.3 kb.
“The most abundant frataxin mRNA is a transcript from exon 1 to exon 5a, with a size of 1.3 kb (37).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [37]
Cites
The ferritins: molecular properties, iron storage function and cellular regulation
Harrison, P. M., & Arosio, P. (1996) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/0005-2728(96)00022-9 · Cited by 2,667 · see citing works
Hentze, M. W., & Kühn, L. C. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.16.8175 · Cited by 1,292 · 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
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
Ponka, P. (1997) · Blood · doi:10.1182/blood.v89.1.1 · Cited by 544 · see citing works
Arosio, P., & Levi, S. (2002) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(02)00842-0 · Cited by 543 · see citing works
A human mitochondrial ferritin encoded by an intronless gene
Levi, S., Corsi, B., Bosisio, M., Invernizzi, R., Volz, A., Sanford, D., Arosio, P., & Drysdale, J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.c100141200 · Cited by 400 · see citing works
Yoon, T., & Cowan, J. A. (2003) · Journal of the American Chemical Society · doi:10.1021/ja027967i · Cited by 353 · see citing works
An interaction between frataxin and Isu1/Nfs1 that is crucial for Fe/S cluster synthesis on Isu1
Gerber, J., Mühlenhoff, U., & Lill, R. (2003) · EMBO Reports · doi:10.1038/sj.embor.embor918 · Cited by 334 · 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
Maturation of cellular Fe-S proteins: an essential function of mitochondria
Gray, H. B. (2000) · Cited by 307 · 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
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
Oxidoreductases Involved in Cell Carbon Synthesis of Methanobacterium thermoautotrophicum
Zeikus, J. G., Fuchs, G., Kenealy, W. R., & Thauer, R. K. (1977) · Journal of Bacteriology · doi:10.1128/jb.132.2.604-613.1977 · Cited by 237 · 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
[26] Vectors for constitutive and inducible gene expression in yeast
Schena, M., Picard, D., & Yamamoto, K. R. (1991) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(91)94029-c · Cited by 220 · 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
Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia
Cazzola, M., Invernizzi, R., Bergamaschi, G., Levi, S., Corsi, B., Travaglino, E., Rolandi, V., Biasiotto, G., Drysdale, J., & Arosio, P. (2003) · Blood · doi:10.1182/blood-2002-07-2006 · Cited by 205 · see citing works
Assembly and iron-binding properties of human frataxin, the protein deficient in Friedreich ataxia
Cavadini, P. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.3.217 · Cited by 197 · see citing works
Mitochondrial Ferritin: A New Player in Iron Metabolism
Drysdale, J., Arosio, P., Invernizzi, R., Cazzola, M., Volz, A., Corsi, B., Biasiotto, G., & Levi, S. (2002) · Blood Cells, Molecules, and Diseases · doi:10.1006/bcmd.2002.0577 · 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
Park, S., Gakh, O., O’Neill, H. A., Mangravita, A., Nichol, H., Ferreira, G. C., & Isaya, G. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303158200 · Cited by 165 · see citing works
Corsi, B., Cozzi, A., Arosio, P., Drysdale, J., Santambrogio, P., Campanella, A., Biasiotto, G., Albertini, A., & Levi, S. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m105372200 · Cited by 164 · see citing works
Self-citationThe Essential Role of Mitochondria in the Biogenesis of Cellular Iron-Sulfur Proteins
Lill, R., Diekert, K., Kaut, A., Lange, H., Pelzer, W., Prohl, C., & Kispál, G. (1999) · Biological Chemistry · doi:10.1515/bc.1999.147 · Cited by 156 · see citing works
Multiple Pathways for Mineral Core Formation in Mammalian Apoferritin. The Role of Hydrogen Peroxide
Zhao, G., Bou‐Abdallah, F., Arosio, P., Levi, S., Janus-Chandler, C., & Chasteen, N. D. (2003) · Biochemistry · doi:10.1021/bi027357v · Cited by 155 · 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
[3] Aconitases: A class of metalloproteins highly sensitive to nitric oxide synthesis
Drapier, J., & Hibbs, J. B. (1996) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(96)69006-5 · Cited by 145 · 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
Human frataxin maintains mitochondrial iron homeostasis in Saccharomyces cerevisiae
Cavadini, P. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.17.2523 · Cited by 141 · 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
Munujos, P., Collcanti, J., González‐Sastre, F., & Gella, F.-J. (1993) · Analytical Biochemistry · doi:10.1006/abio.1993.1360 · Cited by 126 · see citing works
Ramazzotti, A., Vanmansart, V., & Foury, F. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)01498-4 · Cited by 116 · see citing works
Langlois d'Estaintot, B., Santambrogio, P., Granier, T., Gallois, B., Chevalier, J. M., Précigoux, G., Levi, S., & Arosio, P. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2004.04.036 · Cited by 113 · see citing works
From sideroblastic anemia to the role of mitochondrial DNA mutations in myelodysplastic syndromes
Gattermann, N. (2000) · Leukemia Research · doi:10.1016/s0145-2126(99)00160-5 · Cited by 105 · see citing works
Reduction in frataxin causes progressive accumulation of mitochondrial damage
Karthikeyan, G. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg349 · Cited by 102 · 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
Alcindor, T., & Bridges, K. R. (2002) · British Journal of Haematology · doi:10.1046/j.0007-1048.2002.03378.x · Cited by 84 · 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
Chen, O. S., & Kaplan, J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.11.7626 · Cited by 77 · see citing works
Structure of Frataxin Iron Cores: An X-ray Absorption Spectroscopic Study
Nichol, H., Gakh, O., O’Neill, H. A., Pickering, I. J., Isaya, G., & George, G. N. (2003) · Biochemistry · doi:10.1021/bi027021l · Cited by 68 · see citing works
Corson, L., Folmer, J. S., Strain, J. J., Culotta, V., & Cleveland, D. W. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.39.27590 · Cited by 66 · see citing works
Branda, S. S. (1999) · Human Molecular Genetics · doi:10.1093/hmg/8.6.1099 · Cited by 64 · see citing works
Ponka, P. (1997) · Blood · doi:10.1182/blood.v89.1.1.1_1_25 · Cited by 40 · see citing works
Santos, R., Dancis, A., Eide, D. J., Camadro, J., & Lesuisse, E. (2003) · Biochemical Journal · doi:10.1042/bj20030835 · Cited by 30 · see citing works
A high-throughput screening system for genes extending life-span
Chen, C., Dewaele, S., Braeckman, B. P., Desmyter, L., Verstraelen, J., Borgonie, G., Vanfleteren, J. R., & Contreras, R. (2003) · Experimental Gerontology · doi:10.1016/s0531-5565(03)00186-4 · Cited by 30 · see citing works
Seo, H.-Y., Chung, Y., Kim, S.-J., et al. (2003) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-003-1350-3 · Cited by 19 · see citing works
Regulation of the ferritin H subunit by vitamin B12 (cobalamin) in rat spinal cord
Cairo, G., Ronchi, R., Buccellato, F. R., et al. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10267 · Cited by 11 · see citing works
LANGLOISDESTAINTOT, B. (2004) · Journal of Molecular Biology · doi:10.1016/s0022-2836(04)00477-2 · Cited by 2 · see citing works
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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
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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
Camaschella, C., Campanella, A., De Falco, L., Boschetto, L., Merlini, R., Silvestri, L., Levi, S., & Iolascon, A. (2007) · Blood · doi:10.1182/blood-2007-02-072520 · Cited by 306 · see citing works
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- Authors
- Campanella, A.
- Affiliations
- IRCCS Ospedale San Raffaele (IT)
- Corresponding author
- Campanella, A.
- ORCID
- Campanella, A.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-08-04
- Volume
- 13
- Issue
- 19
- Pages
- 2279-2288
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2164048985
- Cited by
- 109
- References
- 49
- Citations by year
- 2026: 2 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 4 · 2016: 5 · 2015: 3 · 2014: 4 · 2013: 7 · 2012: 6
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Fondazione Pierfranco e Luisa Mariani
- National Institutes of Health
- U.S. Public Health Service (44748)
- National Institute on Aging (AG-15709, R01AG015709)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- mitochondrial ferritin, frataxin, Friedreich's ataxia, mitochondrial iron overload, iron-sulfur enzymes, sideroblastic anemia, mitochondrial DNA integrity, oxidative stress resistance, respiratory deficiency, yeast model
- MeSH terms
- Frataxin, DNA, Mitochondrial, Ferritins, Friedreich Ataxia, Humans, Hydrogen Peroxide, Iron, Iron-Sulfur Proteins, Mitochondria, Saccharomyces cerevisiae, Oxidants, Oxidative Stress, Iron Overload, Iron-Binding Proteins
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