title: Ionizing radiation-induced cell death is partly caused by increase of mitochondrial reactive oxygen species in normal human fibroblast cells.
abstract: Radiation-induced cell death is thought to be caused by nuclear DNA damage that cannot be repaired. However, in this study we found that a delayed increase of mitochondrial reactive oxygen species (ROS) is responsible for some of the radiation-induced cell death in normal human fibroblast cells. We have previously reported that there is a delayed increase of mitochondrial (·)O2(-), measured using MitoSOX™ Red reagent, due to gamma irradiation. This is dependent on Drp1 localization to mitochondria. Here, we show that knockdown of Drp1 expression reduces the level of DNA double-strand breaks (DSBs) remaining 3 days after 6 Gy irradiation. Furthermore, cells with knockdown of Drp1 expression are more resistant to gamma radiation. We then tested whether the delayed increase of ROS causes DNA damage. The antioxidant, 2-glucopyranoside ascorbic acid (AA-2G), was applied before or after irradiation to inhibit ROS production during irradiation or to inhibit delayed ROS production from mitochondria. Interestingly, 1 h after exposure, the AA-2G treatment reduced the level of DSBs remaining 3 days after 6 Gy irradiation. In addition, irradiated AA-2G-treated cells were more resistant to radiation than the untreated cells. These results indicate that delayed mitochondrial ROS production may cause some of the cell death after irradiation.
authors: a  Department of Radiology, School of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu City, Oita, Japan;
authors: Shinko
authors: S
authors: Kobashigawa
authors: Genro
authors: G
authors: Kashino
authors: Keiji
authors: K
authors: Suzuki
authors: Shunichi
authors: S
authors: Yamashita
authors: Hiromu
authors: H
authors: Mori
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D034281:Dynamins; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D020558:GTP Phosphohydrolases / Q000172:deficiency / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects*; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000528:radiation effects; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000975:Antioxidants; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C065378:ascorbic acid 2-O-glucoside; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins; D001205:Ascorbic Acid