Shimura Tsutomu, Sasatani Megumi, Kawai Hidehiko, Kamiya Kenji, Kobayashi Junya, Komatsu Kenshi, Kunugita Naoki
a Department of Environmental Health , National Institute of Public Health , Wako , Saitama , Japan.
b Department of Experimental Oncology , Research Center for Radiation Genome Medicine, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University , Hiroshima , Japan.
Cell Cycle. 2017 Mar 19;16(6):565-573. doi: 10.1080/15384101.2017.1284716. Epub 2017 Jan 24.
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.
线粒体在应激反应过程中对维持细胞稳态起着关键作用，而线粒体功能障碍与癌症发生、衰老及神经疾病有关。我们在此研究了电离辐射（IR）对人神经祖干细胞（NSCs）、其分化后的细胞以及人正常成纤维细胞中线粒体的损伤情况。低剂量X射线进行为期31天的长期分次照射（FR）增强了线粒体活性，线粒体膜电位（ΔΨm）升高以及线粒体复合物IV（细胞色素c氧化酶）活性增强，这表明能够满足分化细胞中慢性DNA损伤反应的能量需求。随后，通过持续激活线粒体氧化磷酸化来降低抗氧化剂谷胱甘肽，会在长期接受FR照射的分化细胞中引发氧化应激和基因组不稳定。相比之下，长期FR对NSCs的线粒体活性没有影响。这种细胞类型显示出高效的DNA修复能力，没有线粒体损伤，并且对长期FR具有抗性。在高剂量急性单次照射（SR）（>5 Gy）后，在NSCs和人成纤维细胞中观察到细胞周期停滞在G2期。在这种情况下，在没有增强线粒体活性的情况下，观察到线粒体质量、线粒体DNA和细胞内活性氧（ROS）水平增加。因此，高剂量SR在分化细胞中诱导了细胞衰老。总之，我们证明了线粒体的辐射反应根据DNA损伤程度、辐射暴露持续时间和细胞分化情况而有所不同。
