Small-Molecule Mn Antioxidants in Caenorhabditis elegans and Deinococcus radiodurans Supplant MnSOD Enzymes during Aging and Irradiation
ABSTRACT Denham Harman’s oxidative damage theory identifies superoxide (O2•−) radicals as central agents of aging and radiation injury, with Mn2+-dependent superoxide dismutase (MnSOD) as the principal O2•−-scavenger. However, in the radiation-resistant nematode Caenorhabditis elegans, the mitochond...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-02-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03394-21 |
| _version_ | 1819279448560631808 |
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| author | Elena K. Gaidamakova Ajay Sharma Vera Y. Matrosova Olga Grichenko Robert P. Volpe Rok Tkavc Isabel H. Conze Polina Klimenkova Irina Balygina William H. Horne Cene Gostinčar Xiao Chen Kira S. Makarova Igor Shuryak Chandra Srinivasan Belinda Jackson-Thompson Brian M. Hoffman Michael J. Daly |
| author_facet | Elena K. Gaidamakova Ajay Sharma Vera Y. Matrosova Olga Grichenko Robert P. Volpe Rok Tkavc Isabel H. Conze Polina Klimenkova Irina Balygina William H. Horne Cene Gostinčar Xiao Chen Kira S. Makarova Igor Shuryak Chandra Srinivasan Belinda Jackson-Thompson Brian M. Hoffman Michael J. Daly |
| author_sort | Elena K. Gaidamakova |
| collection | DOAJ |
| description | ABSTRACT Denham Harman’s oxidative damage theory identifies superoxide (O2•−) radicals as central agents of aging and radiation injury, with Mn2+-dependent superoxide dismutase (MnSOD) as the principal O2•−-scavenger. However, in the radiation-resistant nematode Caenorhabditis elegans, the mitochondrial antioxidant enzyme MnSOD is dispensable for longevity, and in the model bacterium Deinococcus radiodurans, it is dispensable for radiation resistance. Many radiation-resistant organisms accumulate small-molecule Mn2+-antioxidant complexes well-known for their catalytic ability to scavenge O2•−, along with MnSOD, as exemplified by D. radiodurans. Here, we report experiments that relate the MnSOD and Mn-antioxidant content to aging and oxidative stress resistances and which indicate that C. elegans, like D. radiodurans, may rely on Mn-antioxidant complexes as the primary defense against reactive oxygen species (ROS). Wild-type and ΔMnSOD D. radiodurans and C. elegans were monitored for gamma radiation sensitivities over their life spans while gauging Mn2+-antioxidant content by electron paramagnetic resonance (EPR) spectroscopy, a powerful new approach to determining the in vivo Mn-antioxidant content of cells as they age. As with D. radiodurans, MnSOD is dispensable for radiation survivability in C. elegans, which hyperaccumulates Mn-antioxidants exceptionally protective of proteins. Unexpectedly, ΔMnSOD mutants of both the nematodes and bacteria exhibited increased gamma radiation survival compared to the wild-type. In contrast, the loss of MnSOD renders radiation-resistant bacteria sensitive to atmospheric oxygen during desiccation. Our results support the concept that the disparate responses to oxidative stress are explained by the accumulation of Mn-antioxidant complexes which protect, complement, and can even supplant MnSOD. IMPORTANCE The current theory of cellular defense against oxidative damage identifies antioxidant enzymes as primary defenders against ROS, with MnSOD being the preeminent superoxide (O2•−) scavenger. However, MnSOD is shown to be dispensable both for radiation resistance and longevity in model organisms, the bacterium Deinococcus radiodurans and the nematode Caenorhabditis elegans. Measured by electron paramagnetic resonance (EPR) spectroscopy, small-molecule Mn-antioxidant content was shown to decline in unison with age-related decreases in cell proliferation and radioresistance, which again are independent of MnSOD presence. Most notably, the Mn-antioxidant content of C. elegans drops precipitously in the last third of its life span, which links with reports that the steady-state level of oxidized proteins increases exponentially during the last third of the life span in animals. This leads us to propose that global responses to oxidative stress must be understood through an extended theory that includes small-molecule Mn-antioxidants as potent O2•−-scavengers that complement, and can even supplant, MnSOD. |
| first_indexed | 2024-12-24T00:28:04Z |
| format | Article |
| id | doaj.art-3b19f3c856f54017b234c6c3990cc6db |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-24T00:28:04Z |
| publishDate | 2022-02-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-3b19f3c856f54017b234c6c3990cc6db2022-12-21T17:24:21ZengAmerican Society for MicrobiologymBio2150-75112022-02-0113110.1128/mbio.03394-21Small-Molecule Mn Antioxidants in Caenorhabditis elegans and Deinococcus radiodurans Supplant MnSOD Enzymes during Aging and IrradiationElena K. Gaidamakova0Ajay Sharma1Vera Y. Matrosova2Olga Grichenko3Robert P. Volpe4Rok Tkavc5Isabel H. Conze6Polina Klimenkova7Irina Balygina8William H. Horne9Cene Gostinčar10Xiao Chen11Kira S. Makarova12Igor Shuryak13Chandra Srinivasan14Belinda Jackson-Thompson15Brian M. Hoffman16Michael J. Daly17Department of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USADepartment of Chemistry, Northwestern University, Evanston, Illinois, USADepartment of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USADepartment of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USADepartment of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USADepartment of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USADepartment of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USADepartment of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USADepartment of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USADepartment of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USADepartment of Biology, University of Ljubljana, Biotechnical Faculty, Ljubljana, SloveniaIGM Biosciences, Mountain View, California, USANational Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USACenter for Radiological Research, Columbia University Irving Medical Center, New York, New York, USADepartment of Chemistry & Biochemistry, California State University, Dominguez Hills, California, USADepartment of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USADepartment of Chemistry, Northwestern University, Evanston, Illinois, USADepartment of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USAABSTRACT Denham Harman’s oxidative damage theory identifies superoxide (O2•−) radicals as central agents of aging and radiation injury, with Mn2+-dependent superoxide dismutase (MnSOD) as the principal O2•−-scavenger. However, in the radiation-resistant nematode Caenorhabditis elegans, the mitochondrial antioxidant enzyme MnSOD is dispensable for longevity, and in the model bacterium Deinococcus radiodurans, it is dispensable for radiation resistance. Many radiation-resistant organisms accumulate small-molecule Mn2+-antioxidant complexes well-known for their catalytic ability to scavenge O2•−, along with MnSOD, as exemplified by D. radiodurans. Here, we report experiments that relate the MnSOD and Mn-antioxidant content to aging and oxidative stress resistances and which indicate that C. elegans, like D. radiodurans, may rely on Mn-antioxidant complexes as the primary defense against reactive oxygen species (ROS). Wild-type and ΔMnSOD D. radiodurans and C. elegans were monitored for gamma radiation sensitivities over their life spans while gauging Mn2+-antioxidant content by electron paramagnetic resonance (EPR) spectroscopy, a powerful new approach to determining the in vivo Mn-antioxidant content of cells as they age. As with D. radiodurans, MnSOD is dispensable for radiation survivability in C. elegans, which hyperaccumulates Mn-antioxidants exceptionally protective of proteins. Unexpectedly, ΔMnSOD mutants of both the nematodes and bacteria exhibited increased gamma radiation survival compared to the wild-type. In contrast, the loss of MnSOD renders radiation-resistant bacteria sensitive to atmospheric oxygen during desiccation. Our results support the concept that the disparate responses to oxidative stress are explained by the accumulation of Mn-antioxidant complexes which protect, complement, and can even supplant MnSOD. IMPORTANCE The current theory of cellular defense against oxidative damage identifies antioxidant enzymes as primary defenders against ROS, with MnSOD being the preeminent superoxide (O2•−) scavenger. However, MnSOD is shown to be dispensable both for radiation resistance and longevity in model organisms, the bacterium Deinococcus radiodurans and the nematode Caenorhabditis elegans. Measured by electron paramagnetic resonance (EPR) spectroscopy, small-molecule Mn-antioxidant content was shown to decline in unison with age-related decreases in cell proliferation and radioresistance, which again are independent of MnSOD presence. Most notably, the Mn-antioxidant content of C. elegans drops precipitously in the last third of its life span, which links with reports that the steady-state level of oxidized proteins increases exponentially during the last third of the life span in animals. This leads us to propose that global responses to oxidative stress must be understood through an extended theory that includes small-molecule Mn-antioxidants as potent O2•−-scavengers that complement, and can even supplant, MnSOD.https://journals.asm.org/doi/10.1128/mbio.03394-21ionizing radiationagingdesiccationROSMn antioxidantsMnSOD |
| spellingShingle | Elena K. Gaidamakova Ajay Sharma Vera Y. Matrosova Olga Grichenko Robert P. Volpe Rok Tkavc Isabel H. Conze Polina Klimenkova Irina Balygina William H. Horne Cene Gostinčar Xiao Chen Kira S. Makarova Igor Shuryak Chandra Srinivasan Belinda Jackson-Thompson Brian M. Hoffman Michael J. Daly Small-Molecule Mn Antioxidants in Caenorhabditis elegans and Deinococcus radiodurans Supplant MnSOD Enzymes during Aging and Irradiation mBio ionizing radiation aging desiccation ROS Mn antioxidants MnSOD |
| title | Small-Molecule Mn Antioxidants in Caenorhabditis elegans and Deinococcus radiodurans Supplant MnSOD Enzymes during Aging and Irradiation |
| title_full | Small-Molecule Mn Antioxidants in Caenorhabditis elegans and Deinococcus radiodurans Supplant MnSOD Enzymes during Aging and Irradiation |
| title_fullStr | Small-Molecule Mn Antioxidants in Caenorhabditis elegans and Deinococcus radiodurans Supplant MnSOD Enzymes during Aging and Irradiation |
| title_full_unstemmed | Small-Molecule Mn Antioxidants in Caenorhabditis elegans and Deinococcus radiodurans Supplant MnSOD Enzymes during Aging and Irradiation |
| title_short | Small-Molecule Mn Antioxidants in Caenorhabditis elegans and Deinococcus radiodurans Supplant MnSOD Enzymes during Aging and Irradiation |
| title_sort | small molecule mn antioxidants in caenorhabditis elegans and deinococcus radiodurans supplant mnsod enzymes during aging and irradiation |
| topic | ionizing radiation aging desiccation ROS Mn antioxidants MnSOD |
| url | https://journals.asm.org/doi/10.1128/mbio.03394-21 |
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