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

Abstract:

:Ionizing radiation induces chronic metabolic oxidative stress and a mutator phenotype in hamster fibroblasts that is mediated by H(2)O(2), but the intracellular source of H(2)O(2) 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 20-40% 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 H(2)O(2) 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 H(2)O(2) 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.

journal_name

Radiat Res

journal_title

Radiation research

authors

Dayal D,Martin SM,Owens KM,Aykin-Burns N,Zhu Y,Boominathan A,Pain D,Limoli CL,Goswami PC,Domann FE,Spitz DR

doi

10.1667/RR1617.1

subject

Has Abstract

pub_date

2009-12-01 00:00:00

pages

737-45

issue

6

eissn

0033-7587

issn

1938-5404

journal_volume

172

pub_type

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