A Role for Mitochondrial Dysfunction in Perpetuating Radiation-Induced Genomic Instability

Abstract

Radiation-induced genomic instability (RIGI) manifests as a heritable increased rate of genetic alterations in the progeny of irradiated cells generations after the initial insult. The progeny can show an increased frequency of chromosomal translocations, deletions, mutations, micronuclei, and decreased plating efficiency. What perpetuates RIGI is unclear; however, persistently increased levels of reactive oxygen species (ROS) are frequently associated with genomically unstable clones. Furthermore, addition of free radical scavengers (e.g., DMSO, glycerol, and cationic thiol cysteamine) reduces the incidence of instability after irradiation, implicating a ROS-mediated role in RIGI induction. Because mitochondria are a major natural cellular source of ROS, we tested the hypothesis that mitochondrial dysfunction has a role in maintaining the elevated ROS levels in our irradiated, genetically unstable GM10115 Chinese hamster ovary cells. Amplex Red fluorometry measurements indicate that the relative contribution of uncoupler-sensitive mitochondrial hydrogen peroxide production to total cellular hydrogen peroxide generation is greater in unstable cells. Measurements of mitochondrial DNA levels and cell cytometric fluorescent measurements of Mitotracker Green FM indicate that differences in mitochondrial ROS production are not due to varying mitochondrial levels. However, mitochondrial respiration measured in digitonin-permeabilized cells is impaired in unstable clones. In addition, manganese superoxide dismutase, a major mitochondrial antioxidant enzyme, exhibits increased immunoreactivity but decreased enzyme activity in unstable clones, which along with decreased respiration rates may explain the increased levels of cellular ROS. These studies show that mitochondria from unstable cells are abnormal and likely contribute to the persistent oxidative stress in the unstable clones. (Cancer Res 2006; 66(21): 10377-83)

Rosiglitazone Treatment Prevents Mitochondrial Dysfunction in Mutant Huntingtin-expressing Cells

“…7). For these studies, striatal cells were incubated with 20 M rosiglitazone for 24 h, in the absence or presence of 40 M GW9662 prior to being loaded with MitoGreen, which is used for mitochondrial mass determinations (42,44,45). Confocal images were taken from striatal cells treated with the indicated conditions (Fig.…”

Estresse oxidativo: conceito, implicações e fatores modulatórios

“…Lemon et al 51 demonstraram maiores níveis de 8-Hidroxyl-2'-Deoxyguanosine (8-OHdG), marcador de dano oxidativo ao DNA (ácido nucléico guanina), em ratos submetidos à radiação gama (yH2AX) proveniente de uma fonte radiotiva de césio ( 137 Cs). Outros estudos ratificam o efeito das radiações ionizantes sobre marcadores do estresse oxidativo, sobretudo os referentes ao dano oxidativo ao DNA [52][53][54] , decorrentes dos processos mutagênicos, aberrações cromossô-micas, instabilidade genômica e alterações teloméricas 51 .…”

A comparison of radiation-induced mitochondrial damage between neural progenitor stem cells and differentiated cells

“…6 Mitochondria-mediated cellular signaling, including Mn-superoxide dismutase (MnSOD) and nuclear factor kB (NF-kB), is associated with the nontargeted effects of IR, such as the adaptive response, bystander effect, and genomic instability. 7,8 Upon high dose of IR, mitochondria release cytochrome c to induce apoptosis in irradiated cells. 9 Thus, mitochondria control both the survival and death of cells after IR.…”