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Sensitivity to Low-Dose/Low-LET Ionizing Radiation in Mammalian Cells Harboring Mutations in Succinate Dehydrogenase Subunit C is Governed by Mitochondria-Derived Reactive Oxygen Species.
MedLine Citation:
PMID:  21083040     Owner:  NLM     Status:  Publisher    
Abstract It has been hypothesized that ionizing radiation-induced disruptions in mitochondrial O(2) metabolism lead to persistent heritable increases in steady-state levels of intracellular superoxide (O(2)(•-)) and hydrogen peroxide (H(2)O(2)) that contribute to the biological effects of radiation. Hamster fibroblasts (B9 cells) expressing a mutation in the gene coding for the mitochondrial electron transport chain protein succinate dehydrogenase subunit C (SDHC) demonstrate increases in steady-state levels of O(2)(•-) and H(2)O(2). When B9 cells were exposed to low-dose/low-LET radiation (5-50 cGy), they displayed significantly increased clonogenic cell killing compared with parental cells. Clones derived from B9 cells overexpressing a wild-type human SDHC (T4, T8) demonstrated significantly increased surviving fractions after exposure to 5-50 cGy relative to B9 vector controls. In addition, pretreatment with polyethylene glycol-conjugated CuZn superoxide dismutase and catalase as well as adenoviral-mediated overexpression of MnSOD and/or mitochondria-targeted catalase resulted in significantly increased survival of B9 cells exposed to 10 cGy ionizing radiation relative to vector controls. Adenoviral-mediated overexpression of either MnSOD or mitochondria-targeted catalase alone was equally as effective as when both were combined. These results show that mammalian cells over expressing mutations in SDHC demonstrate low-dose/low-LET radiation sensitization that is mediated by increased levels of O(2)(•-) and H(2)O(2). These results also support the hypothesis that mitochondrial O(2)(•-) and H(2)O(2) originating from SDH are capable of playing a role in low-dose ionizing radiation-induced biological responses.
Nukhet Aykin-Burns; Benjamin G Slane; Annie T Y Liu; Kjerstin M Owens; Malinda S O'Malley; Brian J Smith; Frederick E Domann; Douglas R Spitz
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2010-11-17
Journal Detail:
Title:  Radiation research     Volume:  -     ISSN:  1938-5404     ISO Abbreviation:  -     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-18     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0401245     Medline TA:  Radiat Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
a Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa 52242.
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