Mitochondrial Damage Response and Fate of Normal Cells Exposed to FLASH Irradiation with Protons.
Mitochondrial Damage Response and Fate of Normal Cells Exposed to FLASH Irradiation with Protons.
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DOI：
10.1667/rade-21-00181.1
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发表时间：
2022-06-01
影响因子：
3.4
通讯作者：
Hei, Tom K.
中科院分区：
文献类型：
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作者：
Guo, Ziyang;Buonanno, Manuela;Harken, Andrew;Zhou, Guangming;Hei, Tom K.
放射治疗(RT)在肿瘤治疗中发挥着重要作用。然而，放射治疗的临床疗效受到受照射肿瘤周围正常组织毒性的限制。与传统放射治疗(CONV-RT)相比，剂量通常以0.03-0.05GY/S之间的剂量率提供，有证据表明，以高出数量级的剂量率提供的辐射(称为闪光-RT)，在实现类似的肿瘤控制的同时，显著减少了正常组织的不良副作用。本研究聚焦于正常细胞的反应，并验证了质子闪光照射通过诱导磷酸化的DRp1来保护正常细胞线粒体功能的假说。用质子(LET=10keV/μm)以0.33GY/S或100GY/S剂量率照射人肺成纤维细胞(IMR90)，观察其线粒体动力学、功能、细胞生长和蛋白质表达水平的变化。与低剂量率质子照射相比，闪光RT可防止线粒体损伤，其特征为形态改变、功能改变(膜电位、mtDNA拷贝数和氧化酶水平)和氧自由基的产生。Conv-RT后，磷酸化形式的Dynamin-1样蛋白(p-Drp1)发生去磷酸化并聚集到线粒体中，导致线粒体分裂和随后的细胞死亡。相比之下，在给予类似闪光剂量后，p-Drp1蛋白水平没有显著变化。与常规照射相比，使用质子的闪光照射对线粒体的损伤最小；我们的结果强调了DRp1介导的线粒体稳态在这一潜在的新的癌症治疗方式中的可能贡献。
Radiation therapy (RT) plays an important role in cancer treatment. The clinical efficacy of radiation therapy is, however, limited by normal tissue toxicity in areas surrounding the irradiated tumor. Compared to conventional radiation therapy (CONV-RT) in which doses are typically delivered at dose rates between 0.03–0.05 Gy/s, there is evidence that radiation delivered at dose rates of orders of magnitude higher (known as FLASH-RT), dramatically reduces the adverse side effects in normal tissues while achieving similar tumor control. The present study focused on normal cell response and tested the hypothesis that proton-FLASH irradiation preserves mitochondria function of normal cells through the induction of phosphorylated Drp1. Normal human lung fibroblasts (IMR90) were irradiated under ambient oxygen concentration (21%) with protons (LET = 10 keV/μm) delivered at dose rates of either 0.33 Gy/s or 100 Gy/s. Mitochondrial dynamics, functions, cell growth and changes in protein expression levels were investigated. Compared to lower dose-rate proton irradiation, FLASH-RT prevented mitochondria damage characterized by morphological changes, functional changes (membrane potential, mtDNA copy number and oxidative enzyme levels) and oxyradical production. After CONV-RT, the phosphorylated form of Dynamin-1-like protein (p-Drp1) underwent dephosphorylation and aggregated into the mitochondria resulting in mitochondria fission and subsequent cell death. In contrast, p-Drp1 protein level did not significantly change after delivery of similar FLASH doses. Compared with CONV irradiation, FLASH irradiation using protons induces minimal mitochondria damage; our results highlight a possible contribution of Drp1-mediated mitochondrial homeostasis in this potential novel cancer treatment modality.