Mitochondrial dysfunction, a probable cause of persistent oxidative stress after exposure to ionizing radiation

Abstract

Several recent studies have suggested that the reactive oxygen species (ROS) generated from mitochondria contribute to genomic instability after exposure of the cells to ionizing radiation, but the mechanism of this process is not yet fully understood. We examined the hypothesis that irradiation induces mitochondrial dysfunction to cause persistent oxidative stress, which contributes to genomic instability. After the exposure of cells to 5 Gy gamma-ray irradiation, we found that the irradiation induced the following changes in a clear pattern of time courses. First, a robust increase of intracellular ROS levels occurred within minutes, but the intracellular ROS disappeared within 30 minutes. Then the mitochondrial dysfunction was detected at 12 hours after irradiation, as indicated by the decreased activity of NADH dehydrogenase (Complex I), the most important enzyme in regulating the release of ROS from the mitochondrial electron transport chain (ETC). Finally, a significant increase of ROS levels in the mitochondria and the oxidation of mitochondrial DNA were observed in cells at 24 hours or later after irradiation.Although further experiments are required, results in this study support the hypothesis that mitochondrial dysfunction causes persistent oxidative stress that may contribute to promote radiation-induced genomic instability.2

Ionizing irradiation-induced radical stress stalls live meiotic chromosome movements by altering the actin cytoskeleton

“…The delayed reoccurrence of ROS-expressing cells may be due to endogenous ROS, e.g. from IR-damaged mitochondria (38,39).…”

Redox-Mediated and Ionizing-Radiation-Induced Inflammatory Mediators in Prostate Cancer Development and Treatment

“…NOX is responsible, in part, for a late increase in intracellular superoxide generation after exposure to IR (32,179). IR-induced mitochondrial dysfunction, especially decreased electron transport chain complex I activity, produces a feed forward loop that contributes to persistent oxidative stress after irradiation (198). Since the mitochondrion is the most important energy-generating organelle, mitochondrial dysfunction due to direct effects of IR or indirect effects mediated by ROS may result in alteration or adaptive responses of metabolic pathways involved in cancer development.…”

“…ROS-induced mtDNA damage can alter polypeptides encoded by mtDNA for respiratory complexes, resulting in additional decreased electron transfer activity and increased ROS generation, thereby establishing a vicious cycle of oxidative stress (102) and decline in mitochondria energy production after initial oxidative damage of mtDNA (101). Mitochondrial dysfunction that causes persistent oxidative stress may contribute to radiation-induced genomic instability (198).…”

The potential benefits of nicaraven to protect against radiation-induced injury in hematopoietic stem/progenitor cells with relative low dose exposures

“…Whole-body radiation was done by exposing the mice to γ-rays with a 137 Cs source in PS-3100SB γ-ray irradiation system (Pony Industry Co., Ltd. Osaka, Japan) [16]. To explore the effect and relevant mechanisms of nicaraven for protecting radiation-induced injury in hematopoietic stem/progenitor cells, mice were daily exposed to 50 mGy γ-rays for 30 days in sequences (cumulative dose of 1.5 Gy).…”

“…To elucidate the relevant mechanism, we measured the intracellular ROS level based on the oxidation of 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H2DCFDA, Molecular Probes Inc.) to form the fluorescent compound 2',7'-dichlorofluorescein (DCF), as described previously [16,18]. Briefly, freshly separated c-kit + cells and c-kit-negative cells were seeded in 96-well culture plates (1x10 4 cells/100 μl/well) and incubated at 37°C in a 5% CO2 incubator for 24 hrs.…”