title: Mitochondrial stress controls the radiosensitivity of the oxygen effect: Implications for radiotherapy.
abstract: It has been more than 60 years since the discovery of the oxygen effect that empirically demonstrates the direct association between cell radiosensitivity and oxygen tension, important parameters in radiotherapy. Yet the mechanisms underlying this principal tenet of radiobiology are poorly understood. Better understanding of the oxygen effect may explain difficulty in eliminating hypoxic tumor cells, a major cause of regrowth after therapy. Our analysis utilizes the Howard-Flanders and Alper formula, which describes the relationship of radiosensitivity with oxygen tension. Here, we assign and qualitatively assess the relative contributions of two important mechanisms. The first mechanism involves the emission of reactive oxygen species from the mitochondrial electron transport chain, which increases with oxygen tension. The second mechanism is related to an energy and repair deficit, which increases with hypoxia. Following a radiation exposure, the uncoupling of the oxidative phosphorylation system (proton leak) in mitochondria lowers the emission of reactive oxygen species which has implications for fractionated radiotherapy, particularly of hypoxic tumors. Our analysis shows that, in oxygenated tumor and normal cells, mitochondria, rather than the nucleus, are the primary loci of radiotherapy effects, especially for low linear energy transfer radiation. Therefore, the oxygen effect can be explained by radiation-induced effects in mitochondria that generate reactive oxygen species, which in turn indirectly target nuclear DNA.
authors.affiliation: Canadian Nuclear Laboratories (CNL), Radiobiology and Health, Chalk River Laboratories, Chalk River, ON, Canada.|McGill Medical Physics Unit, Cedars Cancer Center-Glen Site, Montreal, QC, Canada.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Richardson
authors.affiliation: Department of Biochemistry Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000465:Algorithms; D015687:Cell Hypoxia; D004579:Electron Transport / Q000528:radiation effects; D005057:Eukaryotic Cells / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D000860:Hypoxia; D008928:Mitochondria / Q000378:metabolism* / Q000528:radiation effects; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000528:radiation effects; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D010100:Oxygen
keywords: mitochondria; oxidative stress; oxygen effect; radiation therapy; therapy resistance