Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury

Abstract

Cellular exposure to ionizing radiation leads to oxidizing events that alter atomic structure through direct interactions of radiation with target macromolecules or via products of water radiolysis. Further, the oxidative damage may spread from the targeted to neighboring, non-targeted bystander cells through redox-modulated intercellular communication mechanisms. To cope with the induced stress and the changes in the redox environment, organisms elicit transient responses at the molecular, cellular and tissue levels to counteract toxic effects of radiation. Metabolic pathways are induced during and shortly after the exposure. Depending on radiation dose, dose-rate and quality, these protective mechanisms may or may not be sufficient to cope with the stress. When the harmful effects exceed those of homeostatic biochemical processes, induced biological changes persist and may be propagated to progeny cells. Physiological levels of reactive oxygen and nitrogen species play critical roles in many cellular functions. In irradiated cells, levels of these reactive species may be increased due to perturbations in oxidative metabolism and chronic inflammatory responses, thereby contributing to the long-term effects of exposure to ionizing radiation on genomic stability. Here, in addition to immediate biological effects of water radiolysis on DNA damage, we also discuss the role of mitochondria in the delayed outcomes of ionization radiation. Defects in mitochondrial functions lead to accelerated aging and numerous pathological conditions. Different types of radiation vary in their linear energy transfer (LET) properties, and we discuss their effects on various aspects of mitochondrial physiology. These include short and long-term in vitro and in vivo effects on mitochondrial DNA, mitochondrial protein import and metabolic and antioxidant enzymes.

Figure 1

The direct and indirect cellular effects of ionizing radiation on macromolecules. Absorption of ionizing radiation by living cells directly disrupts atomic structures, producing chemical and biological changes and indirectly through radiolysis of cellular water and generation of reactive chemical species by stimulation of oxidases and nitric oxide synthases. Ionizing radiation may also disrupt mitochondrial functions significantly contributing to persistent alterations in lipids, proteins, nuclear DNA (nDNA) and mitochondrial DNA (mtDNA).

Figure 2. Time scale of events in the radiolysis of water by low linear energy transfer radiations

Figure 3

Ionizing radiation (IR) induces targeted and non-targeted (bystander) effects. Communication of stress-inducing molecules from cells exposed to IR propagates stressful effects, including oxidative stress, to the bystander cells and their progeny. The induced effects may be similar in nature to those observed in progeny of irradiated cells.

Figure 4

Reactive oxygen species (ROS) and the regulation of cell proliferation. Higher or lower than normal levels of ROS can induce cell cycle delays in different phases of the cell cycle.

Figure 5. Schematic of protein import into mitochondria

Figure 6. Native in-gel assay for the mitochondrial (ACO2) and cytoplasmic (IRP1) aconitase activities in control and γ-ray-exposed Chinese hamster lung fibroblasts

Figure 7

Long-term effects of ionizing radiation on protein oxidation. Immunoblots showing protein carbonylation (panel A) and proteins with 4-hydroxynonenal (HNE) adducts (panel B) in progeny of bystander cells that were cultured for 5 h with 1 GeV/nucleon ⁵⁶Fe-irradiated cells. Note that the radiation dose described in the figure refers to the absorbed dose by the irradiated cells.