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.
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June 2022
REGULAR ARTICLES|
March 15 2022
Mitochondrial Damage Response and Fate of Normal Cells Exposed to FLASH Irradiation with Protons
Ziyang Guo;
Ziyang Guo
1
a Center for Radiological Research, College of Physician and Surgeons, Columbia University Medical Center, New York, New York
b State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Institute of Space Life Sciences, Medical College of Soochow University, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, China
c Department of Ultrasound Medicine, Peking University First Hospital, Beijing, China
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Manuela Buonanno;
Manuela Buonanno
1
a Center for Radiological Research, College of Physician and Surgeons, Columbia University Medical Center, New York, New York
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Andrew Harken;
Andrew Harken
a Center for Radiological Research, College of Physician and Surgeons, Columbia University Medical Center, New York, New York
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Guangming Zhou;
Guangming Zhou
2
b State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Institute of Space Life Sciences, Medical College of Soochow University, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou 215123, China
2 Corresponding authors: Tom K. Hei, Columbia University, VC11-218, New York, NY 10032; e-mail: tkh1@cumc.columbia.edu; and Guangming Zhou, Soochow University, 199 Renai Road, Suzhou 215123, China; e-mail: gmzhou@suda.edu.cn.
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Tom K. Hei
Tom K. Hei
2
a Center for Radiological Research, College of Physician and Surgeons, Columbia University Medical Center, New York, New York
2 Corresponding authors: Tom K. Hei, Columbia University, VC11-218, New York, NY 10032; e-mail: tkh1@cumc.columbia.edu; and Guangming Zhou, Soochow University, 199 Renai Road, Suzhou 215123, China; e-mail: gmzhou@suda.edu.cn.
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Radiat Res (2022) 197 (6): 569–582.
Article history
Received:
September 09 2021
Accepted:
February 24 2022
Citation
Ziyang Guo, Manuela Buonanno, Andrew Harken, Guangming Zhou, Tom K. Hei; Mitochondrial Damage Response and Fate of Normal Cells Exposed to FLASH Irradiation with Protons. Radiat Res 1 June 2022; 197 (6): 569–582. doi: https://doi.org/10.1667/RADE-21-00181.1
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