title: Severe mitochondrial damage associated with low-dose radiation sensitivity in ATM- and NBS1-deficient cells.
abstract: Low-dose radiation risks remain unclear owing to a lack of sufficient studies. We previously reported that low-dose, long-term fractionated radiation (FR) with 0.01 or 0.05 Gy/fraction for 31 d inflicts oxidative stress in human fibroblasts due to excess levels of mitochondrial reactive oxygen species (ROS). To identify the small effects of low-dose radiation, we investigated how mitochondria respond to low-dose radiation in radiosensitive human ataxia telangiectasia mutated (ATM)- and Nijmegen breakage syndrome (NBS)1-deficient cell lines compared with corresponding cell lines expressing ATM and NBS1. Consistent with previous results in normal fibroblasts, low-dose, long-term FR increased mitochondrial mass and caused accumulation of mitochondrial ROS in ATM- and NBS1-complemented cell lines. Excess mitochondrial ROS resulted in mitochondrial damage that was in turn recognized by Parkin, leading to mitochondrial autophagy (mitophagy). In contrast, ATM- and NBS1-deficient cells showed defective induction of mitophagy after low-dose, long-term FR, leading to accumulation of abnormal mitochondria; this was determined by mitochondrial fragmentation and decreased mitochondrial membrane potential. Consequently, apoptosis was induced in ATM- and NBS1-deficient cells after low-dose, long-term FR. Antioxidant N-acetyl-L-cysteine was effective as a radioprotective agent against mitochondrial damage induced by low-dose, long-term FR among all cell lines, including radiosensitive cell lines. In conclusion, we demonstrated that mitochondria are target organelles of low-dose radiation. Mitochondrial response influences radiation sensitivity in human cells. Our findings provide new insights into cancer risk estimation associated with low-dose radiation exposure.
authors.affiliation: a Department of Environmental Health , National Institute of Public Health , Wako , Saitama , Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Shimura
authors.affiliation: b Department of Genome Dynamics , Radiation Biology Center, Kyoto University , Kyoto , Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kobayashi
authors.affiliation: b Department of Genome Dynamics , Radiation Biology Center, Kyoto University , Kyoto , Japan.
authors.forename: Kenshi
authors.initials: K
authors.lastname: Komatsu
authors.affiliation: a Department of Environmental Health , National Institute of Public Health , Wako , Saitama , Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kunugita
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000172:deficiency* / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004307:Dose-Response Relationship, Radiation; D006657:Histones / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000528:radiation effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D063306:Mitophagy / Q000187:drug effects / Q000528:radiation effects; D008954:Models, Biological; D009687:Nuclear Proteins / Q000172:deficiency* / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C468783:H2AX protein, human; D006657:Histones; C112156:NBN protein, human; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D064007:Ataxia Telangiectasia Mutated Proteins; D000111:Acetylcysteine
keywords: ATM; NBS1; ROS; low-dose radiation; mitochondria