| Autor: |
Gaidamakova EK; Department of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USA.; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA., Sharma A; Department of Chemistry, Northwestern University, Evanston, Illinois, USA.; Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA., Matrosova VY; Department of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USA.; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA., Grichenko O; Department of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USA.; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA., Volpe RP; Department of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USA.; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA., Tkavc R; Department of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USA.; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.; Department of Microbiology and Immunology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USA., Conze IH; Department of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USA.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.; Institute for Genetics, University of Cologne, Cologne, Germany., Klimenkova P; Department of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USA.; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA., Balygina I; Department of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USA.; Novosibirsk State University, Novosibirsk, Russia., Horne WH; Department of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USA.; Department of Chemistry and Life Science, United States Military Academy, West Point, New York, USA., Gostinčar C; Department of Biology, University of Ljubljana, Biotechnical Faculty, Ljubljana, Slovenia., Chen X; IGM Biosciences, Mountain View, California, USA., Makarova KS; National Center for Biotechnology Informationgrid.419234.9, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA., Shuryak I; Center for Radiological Research, Columbia University Irving Medical Center, New York, New York, USA., Srinivasan C; Department of Chemistry & Biochemistry, California State University, Dominguez Hillsgrid.253556.2, California, USA., Jackson-Thompson B; Department of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USA.; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA., Hoffman BM; Department of Chemistry, Northwestern University, Evanston, Illinois, USA.; Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA., Daly MJ; Department of Pathology, School of Medicine, Uniformed Services University of the Health Sciences (USUHS), Bethesda, Maryland, USA. |
| Abstrakt: |
Denham Harman's oxidative damage theory identifies superoxide (O 2 •- ) radicals as central agents of aging and radiation injury, with Mn 2+ -dependent superoxide dismutase (MnSOD) as the principal O 2 •- -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 Mn 2+ -antioxidant complexes well-known for their catalytic ability to scavenge O 2 •- , 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 Mn 2+ -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 (O 2 •- ) 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 O 2 •- -scavengers that complement, and can even supplant, MnSOD. |
