Influence of Iron Regulation on the Metabolome of Cryptococcus neoformans
Open accessAbstract
Iron is an essential nutrient for virtually all organisms and acts as a cofactor for many key enzymes of major metabolic pathways. Furthermore, iron plays a critical role in pathogen-host interactions. In this study, we analyzed metabolomic changes associated with iron availability and the iron regulatory protein Cir1 in a human fungal pathogen Cryptococcus neoformans. Our metabolite analysis revealed that Cir1 influences the glycolytic pathway, ergosterol biosynthesis and inositol metabolism, which require numerous iron-dependent enzymes and play important roles in pathogenesis and antifungal sensitivity of the fungus. Moreover, we demonstrated that increased cellular iron content and altered gene expression in the cir1 mutant contributed to metabolite changes. Our study provides a new insight into iron regulation and the role of Cir1 in metabolome of C. neoformans.
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An as-yet unknown Fe uptake system independent of the reductive high-affinity iron uptake system may play a role in the acidic host microenvironment in a phagolysosome.
“These observations suggest that an as-yet unknown Fe uptake system, which is independent of the reductive high-affinity iron uptake system, may play a role in the acidic host microenvironment in a phagolysosome [79].”
From Strategies of intracellular pathogens for obtaining iron from the environment (2015) · cites this paper as [79]
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Cites
The Human Serum Metabolome (HUSERMET) Consortium, Dunn, W. B., Broadhurst, D., Begley, P., Zelena, E., Francis-McIntyre, S., Anderson, N., Brown, M., Knowles, J. D., Halsall, A., et al. (2011) · Nature Protocols · doi:10.1038/nprot.2011.335 · Cited by 3,294 · see citing works
Ghannoum, M. A., & Rice, L. B. (1999) · Clinical Microbiology Reviews · doi:10.1128/cmr.12.4.501 · Cited by 1,788 · see citing works
Human metabolic phenotype diversity and its association with diet and blood pressure
Holmes, E., Loo, R. L., Stamler, J., Bictash, M., Yap, I. K. S., Chan, Q., Ebbels, T., De Iorio, M., Brown, I. J., Veselkov, K. A., et al. (2008) · Nature · doi:10.1038/nature06882 · Cited by 1,054 · see citing works
Schaible, U. E., & Kaufmann, S. H. E. (2004) · Nature Reviews Microbiology · doi:10.1038/nrmicro1046 · Cited by 945 · see citing works
Potential Role of Phospholipases in Virulence and Fungal Pathogenesis
Ghannoum, M. A. (2000) · Clinical Microbiology Reviews · doi:10.1128/cmr.13.1.122-143.2000 · Cited by 814 · see citing works
Tikunov, Y. M., Lommen, A., Vos, C. H. R. D., Verhoeven, H. A., Bino, R. J., Hall, R. D., & Bovy, A. G. (2005) · PLANT PHYSIOLOGY · doi:10.1104/pp.105.068130 · Cited by 511 · see citing works
Processing methods for differential analysis of LC/MS profile data
Katajamaa, M., & Orešič, M. (2005) · BMC Bioinformatics · doi:10.1186/1471-2105-6-179 · Cited by 400 · see citing works
Puig, S., Askeland, E., & Thiele, D. J. (2005) · Cell · doi:10.1016/j.cell.2004.11.032 · Cited by 382 · see citing works
Iron uptake in fungi: a system for every source
Philpott, C. C. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.05.008 · Cited by 289 · see citing works
Jung, W. H., Sham, A. P., White, R., & Kronstad, J. W. (2006) · PLoS Biology · doi:10.1371/journal.pbio.0040410 · Cited by 222 · see citing works
Self-citationChoi, Y., Kim, H., Hazekamp, A., Erkelens, C., Lefeber, A., & Verpoorte, R. (2004) · Journal of Natural Products · doi:10.1021/np049919c · Cited by 186 · see citing works
Xue, C., Tada, Y., Dong, X., & Heitman, J. (2007) · Cell Host & Microbe · doi:10.1016/j.chom.2007.05.005 · Cited by 182 · see citing works
Metabolic response to iron deficiency in Saccharomyces cerevisiae
Shakoury-Elizeh, M., Protchenko, O., Berger, A., Cox, J., Gable, K., Dunn, T. M., Prinz, W. A., Bard, M., & Philpott, C. C. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.091710 · Cited by 182 · see citing works
Coordination of Lipid Metabolism in Membrane Biogenesis
Nohturfft, A., & Zhang, S. C. (2009) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.24.110707.175344 · Cited by 175 · see citing works
Iron Source Preference and Regulation of Iron Uptake in Cryptococcus neoformans
Jung, W. H., Sham, A. P., Lian, T., Singh, A., Kosman, D. J., & Kronstad, J. W. (2008) · PLoS Pathogens · doi:10.1371/journal.ppat.0040045 · Cited by 158 · see citing works
Self-citationRoles for inositol-phosphoryl ceramide synthase 1 (IPC1) in pathogenesis ofC. neoformansPreprint
Luberto, C., Toffaletti, D. L., Wills, E. A., Tucker, S. C., Casadevall, A., Perfect, J. R., Hannun, Y. A., & Poeta, M. D. (2001) · Genes & Development · doi:10.1101/gad.856001 · Cited by 150 · see citing works
Gao, X., Pujos‐Guillot, E., Martin, J., Galan, P., Juste, C., Jia, W. P., & Sébédio, J. (2009) · Analytical Biochemistry · doi:10.1016/j.ab.2009.06.036 · Cited by 141 · see citing works
Myo-inositol transport in the central nervous system
Spector, R., & Lorenzo, A. V. (1975) · American Journal of Physiology-Legacy Content · doi:10.1152/ajplegacy.1975.228.5.1510 · Cited by 125 · see citing works
Kusano, M., Fukushima, A., Arita, M., Jonsson, P., Möritz, T., Kobayashi, M., Hayashi, N., Tohge, T., & Saito, K. (2007) · BMC Systems Biology · doi:10.1186/1752-0509-1-53 · Cited by 121 · see citing works
Role of Ferroxidases in Iron Uptake and Virulence of Cryptococcus neoformans
Jung, W. H., Hu, G., Kuo, W., & Kronstad, J. W. (2009) · Eukaryotic Cell · doi:10.1128/ec.00166-09 · Cited by 120 · see citing works
Self-citationScherling, C., Roscher, C., Giavalisco, P., Schulze, E., & Weckwerth, W. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012569 · Cited by 113 · see citing works
Shea, J. M., Kechichian, T. B., Luberto, C., & Del Poeta, M. (2006) · Infection and Immunity · doi:10.1128/iai.00768-06 · Cited by 110 · see citing works
Villas-Bôas, S. G., Noel, S. J., Lane, G. A., Attwood, G. T., & Cookson, A. L. (2005) · Analytical Biochemistry · doi:10.1016/j.ab.2005.11.019 · Cited by 108 · see citing works
Metabolic remodeling in iron-deficient fungi
Philpott, C. C., Leidgens, S., & Frey, A. G. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.01.012 · Cited by 106 · see citing works
Reynolds, T. B. (2009) · Microbiology · doi:10.1099/mic.0.025718-0 · Cited by 92 · see citing works
Hitchcock, C. A., Barrett-Bee, K. J., & Russell, N. J. (1987) · Medical Mycology · doi:10.1080/02681218780000041 · Cited by 80 · see citing works
Xue, C., Liu, T., Chen, L., Li, W., Liu, I., Kronstad, J. W., Seyfang, A., & Heitman, J. (2010) · mBio · doi:10.1128/mbio.00084-10 · Cited by 70 · see citing works
Navigating the Human Metabolome for Biomarker Identification and Design of Pharmaceutical Molecules
Kouskoumvekaki, I., & Panagiotou, G. (2010) · Journal of Biomedicine and Biotechnology · doi:10.1155/2011/525497 · Cited by 56 · see citing works
The origin of myo‐inositol in brain, cerebrospinal fluid and choroid plexus
Spector, R., & Lorenzo, A. V. (1975) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1975.tb06980.x · Cited by 49 · see citing works
Chen, Y.-L., Kauffman, S., & Reynolds, T. B. (2008) · Infection and Immunity · doi:10.1128/iai.01514-07 · Cited by 47 · see citing works
Kim, D., Jarvis, R. M., Yun Xu, A., Oliver, A. W., Allwood, J. W., Hampson, L., HAMPSON, I. N., & Goodacre, R. (2010) · The Analyst · doi:10.1039/b923046g · Cited by 38 · see citing works
Two Major Inositol Transporters and Their Role in Cryptococcal Virulence
Wang, Y., Liu, T., Delmas, G., Park, S., Perlin, D. S., & Xue, C. (2011) · Eukaryotic Cell · doi:10.1128/ec.00327-10 · Cited by 37 · see citing works
Cerebrospinal fluid and plasma distribution of myo-inositol and other polyols in Alzheimer disease
Shetty, H. U., Holloway, H. W., & Schapiro, M. B. (1996) · Clinical Chemistry · doi:10.1093/clinchem/42.2.298 · Cited by 33 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Chen, L., Lin, C., & Chung, K.-R. (2013) · Molecular Plant Pathology · doi:10.1111/mpp.12021 · Cited by 107 · see citing works
The Tools for Virulence of Cryptococcus neoformans
Coelho, C., Bocca, A. L., & Casadevall, A. (2014) · Advances in applied microbiology · doi:10.1016/b978-0-12-800261-2.00001-3 · Cited by 98 · see citing works
An encapsulation of iron homeostasis and virulence in Cryptococcus neoformans
Kronstad, J. W., Hu, G., & Jung, W. H. (2013) · Trends in Microbiology · doi:10.1016/j.tim.2013.05.007 · Cited by 78 · see citing works
Self-citationStrategies of intracellular pathogens for obtaining iron from the environment
Leon-Sicairos, N., Reyes-Cortes, R., Guadrón-Llanos, A. M., Madueña-Molina, J., Leon-Sicairos, C., & Canizalez-Román, A. (2015) · BioMed Research International · doi:10.1155/2015/476534 · Cited by 51 · see citing works
“These observations suggest that an as-yet unknown Fe uptake system, which is independent of the reductive high-affinity iron uptake system, may play a role in the acidic host microenvironment in a phagolysosome [79].”
BackgroundInfluentialSystems Biology Approaches for Host–Fungal Interactions: An Expanding Multi-Omics Frontier
Culibrk, L., Croft, C. A., & Tebbutt, S. J. (2016) · OMICS A Journal of Integrative Biology · doi:10.1089/omi.2015.0185 · Cited by 48 · see citing works
Atanasova‐Pénichon, V., Legoahec, L., Bernillon, S., Deborde, C., Maucourt, M. M., Verdal-Bonnin, M.-N., Pinson‐Gadais, L., Ponts, N., Moing, A., & Richard-Forget, F. C. (2018) · Applied and Environmental Microbiology · doi:10.1128/aem.01705-17 · Cited by 44 · see citing works
Regulatory and pathogenic mechanisms in response to iron deficiency and excess in fungi
Pijuan, J., Moreno, D. F., Yahya, G., Moisa, M., Ul Haq, I., Krukiewicz, K., Mosbah, R., Metwally, K., & Cavalu, S. (2023) · Microbial Biotechnology · doi:10.1111/1751-7915.14346 · Cited by 37 · see citing works
Li, Y., Wang, Z., Liu, X., Song, Z., Li, R., Shao, C., & Yin, Y. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.00931 · Cited by 34 · see citing works
Liew, K. L., Jee, J. M., Yap, I. K. S., & Yong, P. V. C. (2016) · PLoS ONE · doi:10.1371/journal.pone.0153356 · Cited by 33 · see citing works
Catch the wave: Metabolomic analyses in human pathogenic fungi
Brandt, P., Garbe, E., & Vylkova, S. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1008757 · Cited by 29 · see citing works
Metabolic Plasticity of Candida albicans in Response to Different Environmental Conditions
Gallo, M. L., Giovati, L., Magliani, W., Pertinhez, T. A., Conti, S., Ferrari, E., Spisni, A., & Ciociola, T. (2022) · Journal of Fungi · doi:10.3390/jof8070723 · Cited by 29 · see citing works
Iron acquisition in the human fungal pathogen Cryptococcus neoformans
Jung, W. H., & Do, E. (2013) · Current Opinion in Microbiology · doi:10.1016/j.mib.2013.07.008 · Cited by 18 · see citing works
Do, E., Park, M., Hu, G., Caza, M., Kronstad, J. W., & Jung, W. H. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.06.123 · Cited by 18 · see citing works
Self-citationJung, W. H., Sánchez‐León, E., & Kronstad, J. W. (2021) · Current Genetics · doi:10.1007/s00294-021-01172-5 · Cited by 17 · see citing works
Self-citationLiras, P., & Martin, J. F. (2023) · Antibiotics · doi:10.3390/antibiotics12010159 · Cited by 14 · see citing works
Suo, C., Ma, L., Li, H., Sun, J., Li, C., Lin, M., Sun, T., Du, W., Li, Y., Gao, X., et al. (2017) · MicrobiologyOpen · doi:10.1002/mbo3.564 · Cited by 11 · see citing works
Allergen1 regulates polysaccharide structure in C ryptococcus neoformans
Jain, N., Cordero, R. J. B., Casadevall, A., & Fries, B. C. (2013) · Molecular Microbiology · doi:10.1111/mmi.12216 · Cited by 5 · see citing works
Inhibition of respiration prompts commitment to unisexual reproduction in Cryptococcus deneoformans
Yao, X., Tian, X., Liu, H., He, G.-J., Chen, L., Shen, L., Teng, J., Chen, X., Hussein, M., Gherbawy, Y. A. M. H., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116603
- Authors
- Choi, J. N., Kim, J., Kim, J., Jung, W. H., & Lee, C. H.
- Affiliations
- Konkuk University (KR)
- Chung-Ang University (KR)
- Corresponding author
- Lee, Choong Hwan
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-07-23
- Volume
- 7
- Issue
- 7
- Pages
- e41654
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3402442
- OpenAlex
- W2034922205
- Cited by
- 18
- References
- 33
- Citations by year
- 2025: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2018: 1 · 2017: 1 · 2016: 4 · 2015: 1 · 2014: 1 · 2013: 4
- FWCI
- 1.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Research Foundation (2010-0019306)
- National Research Foundation of Korea (2010-0019306, 2010-0027204)
- Ministry of Education, Science and Technology (2010-0019306)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Keywords
- Cryptococcus neoformans, iron regulation, iron regulatory proteins, metabolome, glycolysis, ergosterol biosynthesis, inositol metabolism, antifungal susceptibility, fungal pathogenesis, iron-dependent enzymes
- MeSH terms
- Antifungal Agents, Azoles, Cryptococcus neoformans, Ergosterol, Fungal Proteins, Glycolysis, Humans, Inositol, Iron, Microbial Sensitivity Tests, Mutation, Mass Spectrometry, Discriminant Analysis, Least-Squares Analysis, Principal Component Analysis, Iron-Regulatory Proteins, Metabolomics, Metabolome
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