PDF file - 18K, Supplementary Figure S2. Dose response survival of SAE cells treated with graded doses of mdivi-1 for either 6 or 12 hours based on the MTT assay. Result indicated that a 50 microM dose of mdivi-1 has no obvious toxicity to SEA cells following a 6 hour treatment. # p <0.01, versus the control group. Bars indicate plus-minus SD. Results were pooled from three independent experiments.
ARTICLE ABSTRACT
Direct DNA damage is often considered the primary cause of cancer in patients exposed to ionizing radiation or environmental carcinogens. Although mitochondria are known to play an important role in radiation-induced cellular response, the mechanisms by which cytoplasmic stimuli modulate mitochondrial dynamics and functions are largely unknown. In the present study, we examined changes in mitochondrial dynamics and functions triggered by α particle damage to the mitochondria in human small airway epithelial cells, using a precision microbeam irradiator with a beam width of 1 μm. Targeted cytoplasmic irradiation using this device resulted in mitochondrial fragmentation and a reduction of cytochrome c oxidase and succinate dehydrogenase activity, when compared with nonirradiated controls, suggesting a reduction in respiratory chain function. In addition, mitochondrial fragmentation or fission was associated with increased expression of the dynamin-like protein DRP1, which promotes mitochondrial fission. DRP1 inhibition by the drug mdivi-1 prevented radiation-induced mitochondrial fission, but respiratory chain function in mitochondria inhibited by radiation persisted for 12 hours. Irradiated cells also showed an increase in mitochondria-derived superoxide that could be quenched by dimethyl sulfoxide. Taken together, our results provide a mechanistic explanation for the extranuclear, nontargeted effects of ionizing radiation. Cancer Res; 73(22); 6700–10. ©2013 AACR.
