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

• Published in: Radiation research 2011-02, Vol.175 (2), p.150-158
• Main Authors: Aykin-Burns, Nukhet, Slane, Benjamin G., Liu, Annie T. Y., Owens, Kjerstin M., O'Malley, Malinda S., Smith, Brian J., Domann, Frederick E., Spitz, Douglas R.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - radiation effects; Catalase; Cell lines; Cells, Cultured; Cricetinae; Cricetulus; DNA Damage; Enzymes; Genetic mutation; Ionizing radiation; Irradiation; Linear Energy Transfer; Membrane Proteins - genetics; Membrane Proteins - physiology; Mitochondria - metabolism; Mutation; Oxidative stress; Radiation dosage; Radiation Tolerance; Reactive Oxygen Species - metabolism; REGULAR ARTICLES; Space life sciences; Superoxides
• ISSN: 0033-7587; 1938-5404
• DOI: 10.1667/RR2220.1

It has been hypothesized that ionizing radiation-induced disruptions in mitochondrial O2 metabolism lead to persistent heritable increases in steady-state levels of intracellular superoxide (O2•U+2212) and hydrogen peroxide (H2O2) 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 O2•− and H2O2. 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 O2•− and H2O2. These results also support the hypothesis that mitochondrial O2•− and H2O2 originating from SDH are capable of playing a role in low-dose ionizing radiation-induced biological responses.