A comparison of radiation-induced mitochondrial damage between neural progenitor stem cells and differentiated cells
A comparison of radiation-induced mitochondrial damage between neural progenitor stem cells and differentiated cells
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DOI：
10.1080/15384101.2017.1284716
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发表时间：
2017-01
期刊：
影响因子：
4.3
通讯作者：
T. Shimura;M. Sasatani;H. Kawai;K. Kamiya;J. Kobayashi;K. Komatsu;N. Kunugita
中科院分区：
文献类型：
--
作者：
T. Shimura;M. Sasatani;H. Kawai;K. Kamiya;J. Kobayashi;K. Komatsu;N. Kunugita
摘要线粒体在应激反应中维持细胞内环境稳定方面起着关键作用，线粒体功能障碍与肿瘤发生、衰老和神经系统疾病有关。我们在这里研究电离辐射（IR）诱导的线粒体损伤的人神经祖细胞干细胞（NSCs），其分化的同行和人正常的成纤维细胞。长期低剂量X射线分次照射（FR）31 d，线粒体膜电位（Δ Km）和线粒体复合物IV（细胞色素c氧化酶）活性升高，线粒体活性增强，以满足分化细胞慢性DNA损伤反应的能量需求。随后减少的抗氧化剂谷胱甘肽通过连续激活线粒体氧化磷酸化引起氧化应激和基因组的不稳定性在分化的细胞暴露于长期FR。相反，长期FR对神经干细胞的线粒体活性没有影响。这种细胞类型表现出有效的DNA修复，没有线粒体损伤，并长期抵抗FR。在高剂量的急性单次辐射（SR）（> 5戈伊）后，在神经干细胞和人成纤维细胞中观察到细胞周期停滞在G2期。在此条件下，在没有增强的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）水平的增加。因此，在分化的细胞中，高剂量的SR诱导细胞衰老。总之，我们证明了线粒体辐射反应根据DNA损伤的程度、辐射暴露的持续时间和细胞分化而不同。
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.