Mitochondrial complex II dysfunction can contribute significantly to genomic instability after exposure to ionizing radiation

Disha Dayal, Sean M. Martin, Kjerstin M. Owens, Nukhet Aykin-Burns, Yueming Zhu, Amutha Boominathan, Debkumar Pain, Charles L. Limoli, Prabhat C. Goswami, Frederick E. Domann, Douglas R. Spitz

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

Dayal, D., Martin, S. M., Owens, K. M., Aykin-Burns, N., Zhu, Y., Boominathan, A., Pain, D., Limoli, C. L., Goswami, P. C., Domann, F. E. and Spitz, D. R. Mitochondrial Complex II Dysfunction Can Contribute Significantly to Genomic Instability after Exposure to Ionizing Radiation. Ionizing radiation induces chronic metabolic oxidative stress and a mutator phenotype in hamster fibroblasts that is mediated by H2O2, but the intracellular source of H2O2 is not well defined. To determine the role of mitochondria in the radiation-induced mutator phenotype, end points of mitochondrial function were determined in unstable (CS-9 and LS-12) and stable (114) hamster fibroblast cell lines derived from GM10115 cells exposed to 10 Gy X rays. Cell lines isolated after irradiation demonstrated a 2040 loss of mitochondrial membrane potential and an increase in mitochondrial content compared to the parental cell line GM10115. Surprisingly, no differences were observed in steady-state levels of ATP (P > 0.05). Unstable clones demonstrated increased oxygen consumption (two-to threefold; CS-9) and/or increased mitochondrial electron transport chain (ETC) complex II activity (twofold; LS-12). Using Western blot analysis and Blue Native gel electrophoresis, a significant increase in complex II subunit B protein levels was observed in LS-12 cells. Furthermore, immunoprecipitation assays revealed evidence of abnormal complex II assembly in LS-12 cells. Treatment of LS-12 cells with an inhibitor of ETC complex II (thenoyltrifluoroacetone) resulted in significant decreases in the steady-state levels of H2O2 and a 50 reduction in mutation frequency as well as a 16 reduction in CAD gene amplification frequency. These data show that radiation-induced genomic instability was accompanied by evidence of mitochondrial dysfunction leading to increased steady-state levels of H2O2 that contributed to increased mutation frequency and gene amplification. These results support the hypothesis that mitochondrial dysfunction originating from complex II can contribute to radiation-induced genomic instability by increasing steady-state levels of reactive oxygen species.

Original languageEnglish (US)
Pages (from-to)737-745
Number of pages9
JournalRadiation Research
Volume172
Issue number6
DOIs
StatePublished - Dec 2009

ASJC Scopus subject areas

  • Biophysics
  • Radiation
  • Radiology Nuclear Medicine and imaging

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    Dayal, D., Martin, S. M., Owens, K. M., Aykin-Burns, N., Zhu, Y., Boominathan, A., Pain, D., Limoli, C. L., Goswami, P. C., Domann, F. E., & Spitz, D. R. (2009). Mitochondrial complex II dysfunction can contribute significantly to genomic instability after exposure to ionizing radiation. Radiation Research, 172(6), 737-745. https://doi.org/10.1667/RR1617.1