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The effects of mitochondrial iron homeostasis on cofactor specificity of superoxide dismutase 2
Open accessAbstract
Many metalloproteins have the capacity to bind diverse metals, but in living cells connect only with their cognate metal cofactor. In eukaryotes, this metal specificity can be achieved through metal-specific metallochaperone proteins. Herein, we describe a mechanism whereby Saccharomyces cerevisiae manganese superoxide dismutase (SOD2) preferentially binds manganese over iron based on the differential bioavailability of these ions within mitochondria. The bulk of mitochondrial iron is normally unavailable to SOD2, but when mitochondrial iron homeostasis is disrupted, for example, by mutations in S. cerevisiae mtm1, ssq1 and grx5, iron accumulates in a reactive form that potently competes with manganese for binding to SOD2, inactivating the enzyme. Studies in mtm1 mutants indicate that iron inactivation of SOD2 involves the Mrs3p/Mrs4p mitochondrial carriers and iron-binding frataxin (Yfh1p). A small pool of SOD2-reactive iron also exists under normal iron homeostasis conditions and binds SOD2 when mitochondrial manganese is low. The ability to control this reactive pool of iron is critical to maintaining SOD2 activity and has important potential implications for oxidative stress in disorders of iron overload.
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“A molecular cross-talk exists between Mn and Fe in mitochondria, able to switch SOD2 functionality [48,49].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [49]
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Metadata
- Authors
- Yang, M., Cobine, P. A., Molik, S., Naranuntarat, A., Lill, R., Winge, D. R., & Culotta, V. C.
- Affiliations
- Johns Hopkins University (US)
- University of Utah (US)
- Philipps University of Marburg (DE)
- Corresponding author
- Culotta, Valeria C
- Venue
- The EMBO Journal
- Published
- 2006-04-06
- Volume
- 25
- Issue
- 8
- Pages
- 1775-1783
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1440838
- OpenAlex
- W2137209776
- Cited by
- 143
- References
- 64
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 5 · 2023: 2 · 2022: 10 · 2021: 6 · 2020: 5 · 2019: 3 · 2018: 3 · 2017: 10 · 2016: 3 · 2015: 6 · 2014: 10 · 2013: 9 · 2012: 7
- FWCI
- 5.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB593)
- National Institutes of Health
- Leibniz-Gemeinschaft
- National Cancer Institute (CA 61286, R01CA061286)
- National Institute of General Medical Sciences (F32GM074402)
- National Institute of Environmental Health Sciences (ES 07141, R01ES008996, ES08996, T32ES007141)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- manganese superoxide dismutase, mitochondrial iron homeostasis, cofactor specificity, metallochaperone, reactive iron, iron overload, oxidative stress, MTM1, frataxin, Saccharomyces cerevisiae
- MeSH terms
- Frataxin, Superoxide Dismutase 2, Enzyme Activation, Homeostasis, Iron, Manganese, Mitochondria, Mutation, Saccharomyces cerevisiae, Superoxide Dismutase, Transcription Factors, Mitochondrial Proteins, Cation Transport Proteins, Saccharomyces cerevisiae Proteins, Iron-Binding Proteins
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