title: A comparison of radiation-induced mitochondrial damage between neural progenitor stem cells and differentiated cells.
abstract: Mitochondria play a key role in maintaining cellular homeostasis during stress responses, and mitochondrial dysfunction contributes to carcinogenesis, aging, and neurologic disease. We here investigated ionizing radiation (IR)-induced mitochondrial damage in human neural progenitor stem cells (NSCs), their differentiated counterparts and human normal fibroblasts. Long-term fractionated radiation (FR) with low doses of X-rays for 31 d enhanced mitochondrial activity as evident by elevated mitochondrial membrane potential (ΔΨm) and mitochondrial complex IV (cytochrome c oxidase) activity to fill the energy demands for the chronic DNA damage response in differentiated cells. Subsequent reduction of the antioxidant glutathione via continuous activation of mitochondrial oxidative phosphorylation caused oxidative stress and genomic instability in differentiated cells exposed to long-term FR. In contrast, long-term FR had no effect on the mitochondrial activity in NSCs. This cell type showed efficient DNA repair, no mitochondrial damage, and resistance to long-term FR. After high doses of acute single radiation (SR) (> 5 Gy), cell cycle arrest at the G2 phase was observed in NSCs and human fibroblasts. Under this condition, increase in mitochondria mass, mitochondrial DNA, and intracellular reactive oxygen species (ROS) levels were observed in the absence of enhanced mitochondrial activity. Consequently, cellular senescence was induced by high doses of SR in differentiated cells. In conclusion, we demonstrated that mitochondrial radiation responses differ according to the extent of DNA damage, duration of radiation exposure, and cell differentiation.
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 Experimental Oncology , Research Center for Radiation Genome Medicine, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University , Hiroshima , Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Sasatani
authors.affiliation: b Department of Experimental Oncology , Research Center for Radiation Genome Medicine, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University , Hiroshima , Japan.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Kawai
authors.affiliation: b Department of Experimental Oncology , Research Center for Radiation Genome Medicine, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University , Hiroshima , Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kamiya
authors.affiliation: c Department of Genome Dynamics , Radiation Biology Center, Kyoto University , Kyoto , Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kobayashi
authors.affiliation: c 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: D059447:Cell Cycle Checkpoints / Q000528:radiation effects; D002454:Cell Differentiation / Q000528:radiation effects*; D002467:Cell Nucleus / Q000378:metabolism / Q000528:radiation effects; D016922:Cellular Senescence / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D004272:DNA, Mitochondrial / Q000235:genetics; D004307:Dose-Response Relationship, Radiation; D005455:Fluorescent Antibody Technique; D016195:G2 Phase / Q000528:radiation effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000528:radiation effects*; D058953:Neural Stem Cells / Q000378:metabolism* / Q000528:radiation effects*; D010084:Oxidation-Reduction / Q000528:radiation effects; D010085:Oxidative Phosphorylation / Q000528:radiation effects; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; C468783:H2AX protein, human; D006657:Histones; D017382:Reactive Oxygen Species
keywords: ROS; low-dose radiation; mitochondrial damage; neural stem cells; parkin