Switch of Mitochondrial Superoxide Dismutase into a Prooxidant Peroxidase in Manganese-Deficient Cells and Mice
Open accessAbstract
Superoxide radical anion (O 2⋅‒) and other reactive oxygen species are constantly produced during respiration. In mitochondria, the dismutation of O 2⋅‒ is accelerated by the mitochondrial superoxide dismutase 2 (SOD2), an enzyme that has been traditionally associated with antioxidant protection. However, increases in SOD2 expression promote oxidative stress, indicating that there may be a prooxidant role for SOD2. Here we show that SOD2, which normally binds manganese, can incorporate iron and generate an alternative isoform with peroxidase activity. The switch from manganese to iron allows FeSOD2 to utilize H 2 O 2 to promote oxidative stress. We found that FeSOD2 is formed in cultured cells and in vivo. FeSOD2 causes mitochondrial dysfunction and higher levels of oxidative stress in cultured cells and in vivo. We show that formation of FeSOD2 converts an antioxidant defense into a prooxidant peroxidase that leads to cellular changes seen in multiple human diseases.
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When a switch from Mn2+ to Fe2+ in SOD2 occurs, the new FeSOD2 turns its function towards a pro-oxidant peroxidase and is a powerful causative factor of OS, mitochondria functional impairment and senescence.
“When a switch from manganese (Mn2+) to iron (Fe2+) in SOD2 occurs, usually when due to a depletion Mn2+ is replaced by Fe2+, the new FeSOD2, which turns its function towards a pro-oxidant peroxidase, is a powerful causative factor of OS, mitochondria functional impairment and senescence [47].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [47]
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The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence
Varesi, A., Chirumbolo, S., Campagnoli, L. I. M., Pierella, E., Piccini, G. B., Carrara, A., Ricevuti, G., Scassellati, C., Bonvicini, C., & Pascale, A. (2022) · Antioxidants · doi:10.3390/antiox11071224 · Cited by 145 · see citing works
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“described the switch from the anti-oxidative manganese containing MnSOD2 to the iron-containing pro-oxidative FeSOD2 due to the excess of free iron in cell culture or in mice on high iron diet [19].”
Background
- Authors
- Ganini, D., Santos, J. H., Bonini, M. G., & Mason, R. P.
- Affiliations
- National Institutes of Health (US)
- Medical College of Wisconsin (US)
- Corresponding author
- Ganini, Douglas
- Mason, Ronald P.
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2018-04
- Volume
- 25
- Issue
- 4
- Pages
- 413-425.e6
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC5910218
- OpenAlex
- W2786192066
- Cited by
- 59
- References
- 62
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 5 · 2023: 4 · 2022: 9 · 2021: 10 · 2020: 9 · 2019: 4 · 2018: 6
- FWCI
- 2.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (ZIA ES050117, ZIA ES050139)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- manganese deficiency, iron incorporation, peroxidase activity, oxidative stress, reactive oxygen species, mitochondrial dysfunction, antioxidant defense
- MeSH terms
- Superoxide Dismutase 2, Animals, Humans, Hydrogen Peroxide, Iron, Manganese, Mice, Inbred C57BL, Mitochondria, Peroxidase, Superoxide Dismutase, Reactive Oxygen Species, Oxidative Stress, Mice, MCF-7 Cells
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