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.

Mitochondrial adaptation in human mesenchymal stem cells following ionizing radiation

“…Interestingly, Lall et al (61) described an HIF1-dependent metabolic adaptation at 5% O 2 to the adaptive response that involves the induction of a glycolytic program at later time points (12 h). We believe that this adaptation may be attributed to changes in the radiation oxygen effect, in which greater cell death is observed at higher O 2 tension, as previously described by Richardson and Harper (3). Our system differs from that of Lall et al .…”

“…Additionaly, although failing to reach statistical significance, OPA1-KO cells also generally had less γH2AX following IR. This last finding may be related to the oxygen effect, which posits that cells that are less reliant on mitochondria for ATP production are radioresistant because there is less secondary IR damage due in part to lowered induction of mitochondrial ROS (3). Taken together, our data suggest that functional mitochondrial remodeling is required for certain aspects of the biologic responses to IR.…”

Fasting, Fats, and Physics: Combining Ketogenic and Radiation Therapy against Cancer

“…All these mechanisms are consistent with data implying that the mitochondrial location of anti-oxidative enzymes is more cell protective than the cytosolic one, in particular in case of manganese superoxide dismutase (MnSOD) which dismutates superoxide to the less toxic hydrogen peroxide (H 2 O 2 ) [65]. According to Richardson and Harper [66], the mtROS and mtRNS produced through IR could fully account for the majority of nDNA damage and most of the observed RT effects.…”

“…Ionization clusters are also predicted to occur within mitochondria [64], which seems to have much higher relevance for RT outcomes than realized in the past [65,66]. Mitochondrial DNA (mtDNA) is more vulnerable to ionizing radiation than nDNA, due to a lack of histone protection and less efficient repair mechanisms [67,68].…”

“…Recently, Richardson and Harper [66] proposed a 2-component model for the oxygen effect. In their explanation, as oxygen levels rise, damage from increasing levels of mtROS constitutes the main component which is more and more counteracted by more efficient DNA repair due to increasing ATP production.…”