Mutagenesis Advance Access originally published online on October 25, 2006
Mutagenesis 2006 21(6):361-367; doi:10.1093/mutage/gel048
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Mitochondrial dysfunction, persistently elevated levels of reactive oxygen species and radiation-induced genomic instability: a review
1 Graduate Program in Molecular and Cell Biology, University of Maryland Baltimore, 108 North Greene Street, BRF Room 110C, Baltimore, MD 21201, USA 2 Radiation Oncology Research Laboratory 655 West Baltimore Street, Baltimore, MD 21201, USA 3 Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine 655 West Baltimore Street, Baltimore, MD 21201, USA 4 Department of Anesthesiology, University of Maryland School of Medicine 685 West, Baltimore Street, MSTF 5–34, Baltimore, MD 21201, USA
Radiation-induced genomic instability (RIGI) challenges the long-standing notion that radiation's effects derive solely from nuclear impact. In RIGI it is the unirradiated progeny that can display phenotypic changes at delayed times after irradiation of the parental cell. RIGI might well provide the driving force behind the development of radiation-induced tumorigenesis as most cancer cells even in pre-neoplastic states display multiple genetic alterations. Thus, understanding RIGI may help elucidate the mechanisms underlying radiation-induced carcinogenesis. One characteristic of clones of genetically unstable cells is that many exhibit persistently increased levels of reactive oxygen species (ROS). Furthermore, oxidants enhance and antioxidants diminish radiation-induced instability. However, much about the mechanisms behind the initiation and perpetuation of RIGI remains unknown and we examine the evidence for the hypothesis that oxidative stress and mitochondrial dysfunction may be involved in perpetuating the unstable phenotype in some cell clones surviving ionizing radiation.
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Introduction |
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Radiation-induced genomic instability, (RIGI) is a delayed, long-lasting effect of ionizing radiation that manifests in the unirradiated progeny of irradiated cells. What initiates RIGI and causes it to persist over time is unknown but a potential mechanism may be through oxidative stress caused by a high level of reactive oxygen species (ROS). Increased ROS levels have been observed in different radiation-induced genomically unstable cell systems (1
–5). Antioxidants, free-radical scavengers, and hypoxia decrease the incidence of instability (5–7) while chronic hydrogen peroxide or glucose oxidase exposure increase the incidence (2,8). The source of the high and persistent ROS levels characteristic of unstable cells is unknown, and here we present evidence for the hypothesis that the mitochondria are the major cellular sources of ROS associated with RIGI. In an effort to understand the mechanism of RIGI, we will review our current understanding of RIGI, mitochondria and their respective relationships to both oxidative stress and carcinogenesis.
Radiation causes cancer
Radiation is a ‘universal carcinogen’ because of its ability to penetrate cells and induce cancers in most tissues of the body (9,10). The first noted carcinogenic consequences of ionizing radiation were skin cancers resulting from experiments with Roentgen's cathode tube used in an X-ray machine whose beam early radiologists focused using their bare hands. Later, osteosarcomas were recorded in watch factory workers when they unknowingly ingested a radioactive paint containing radium used to make the markings on the watches luminescent. Since then, much data has accumulated on ionizing radiation's carcinogenic potential with perhaps the largest database being the Japanese atomic bomb survivors who showed increased cancer risk in almost all major organs (11).
Non-targeted effects of radiation
Until recently, radiation's carcinogenic potential was believed to result solely from nuclear energy deposition and subsequent misrepair of the genetic damage. An exciting new area of radiation biology has emerged as the result of biological effects being observed in cells whose nuclei were never directly irradiated (12,13). These non-targeted phenomena, defined as heritable genetic changes that are not primarily a result of DNA sequence modification (14), have changed our thinking of the cellular effects of radiation exposure. For example, the development of single cell irradiators, or microbeams, has enabled cytoplasmic irradiation of single cells without nuclear exposure. Wu et al. (15) described increased nuclear mutation frequencies after cytoplasmic irradiation indicating that the target of genetic alterations is larger than the nucleus. Treatment with a free-radical scavenger demonstrated nuclear mutagenicity after cytoplasmic irradiation was mediated by ROS (15). The bystander effect is a non-targeted effect whereby non-irradiated cells manifest many of the phenotypes usually associated with radiation exposure (16). Nagasawa and Little (17) irradiated Chinese hamster ovary cells with very low doses of high LET radiation such that <1% of the nuclei were hit by an alpha particle, yet they observed an increased frequency of sister chromatid exchanges in 
30% of the cell population. Similar to effects observed after cytoplasmic irradiation, this could be inhibited by superoxide dismutase indicating a role for ROS (17). Gap junction communication and soluble factors secreted by the irradiated cell are proposed mechanisms that result in the wide spectrum of phenomena seen in bystander cells (18,19).
RIGI is another non-targeted effect that appears in the progeny of the irradiated cell and is characterized by a heritable increased frequency of genetic alterations occurring at delayed times from the irradiation. Genetic alterations observed as a consequence of RIGI include chromosomal rearrangements, micronuclei, deletions, gene amplifications, mutations and decreased plating efficiency. Chromosomal instability is perhaps the best described of these phenotypes, and while the precise mechanism is unknown, a factor secreted from unstable cells might be involved in perpetuating chromosomal changes through a bystander-like mechanism (reviewed in refs 20,21).
Studies in our laboratory investigating the role of soluble secreted factors in unstable cells led to the discovery of a new non-targeted effect, the death-inducing effect (DIE). To test the hypothesis that unstable cells secrete a factor that perpetuates chromosomal instability, Nagar et al. (22) transferred media from radiation-induced unstable cells onto parental GM10115 cells. They observed almost total cytotoxicity and demonstrated that secreted factors from unstable cells are involved in increasing double-strand breaks, the micronuclei frequency, and eventual apoptosis in parental cells (23,24). Further analysis of DIE suggests that these cytotoxic factors may potentially induce heritable changes that perpetuate instability in some of those occasional surviving cell clones (25).
Mechanistically, we think of it as interesting that DIE is distinct from non-targeted bystander effects described above. While unstable GM10115 cells can exhibit DIE, GM10115 cells do not demonstrate a bystander effect as measured by cell killing after medium transfer experiments. When medium from irradiated GM10115 cells was transferred to non-irradiated GM10115 cells, no effect on cytotoxicity was observed (22). This suggests that GM10115 cells either do not secrete a bystander signal or are not responsive to such secreted signals from irradiated cells. Furthermore it indicates that the DIE factor(s) are likely different from cytotoxic bystander factors. Clearly to understand the mechanisms and significance of both DIE and bystander effects, identification of the factors involved is of utmost importance.
Radiation-induced genomic instability and cancer
The development of the numerous genetic alterations seen in cancer cells cannot be accounted for by independent mutations given the low spontaneous mutation rate (26). Gross genome destabilization following exposure to a DNA damaging agent could facilitate development of the mutations required for carcinogenesis (27). In fact, most cancers display a form of genetic instability resulting in the large number of complex genetic alterations seen in many tumors (28). Instability is observed in pre-malignant states as well, indicating an early role in carcinogenesis. In a study of sporadic colon cancers and pre-neoplastic colon polyps, malignancies in vivo appeared to derive from instability perpetuated over years within the host (29). As genomic instability appears to play a role in carcinogenesis, understanding the initiation and perpetuation of RIGI may lend to the elucidation of the mechanisms of radiation-induced tumor formation (30).
Delayed instability in irradiated cell clones
A number of systems in vivo and in vitro have been studied in efforts to understand the mechanisms of RIGI initiation and perpetuation (reviewed in refs 12,13). The GM10115 Chinese hamster ovary human hybrid cell line used in our laboratory to study chromosomal instability contains 20–24 hamster chromosomes and a single stably integrated human chromosome 4 that we use as a marker for gross chromosomal changes (31). At a relatively high frequency, clonally expanded single cells surviving ionizing radiation demonstrates chromosomal instability indicated in by rearrangements of the human chromosome with the hamster karyotype. These are observed at delayed times after irradiation in the progeny of an irradiated cell and the evolution of novel genomic rearrangements can continue for many years. In addition to chromosome rearrangements, unstable clones derived from GM10115 can, but do not necessarily display other phenotypes: delayed mutation rate, gene amplification, increased micronuclei and persistent oxidative stress (32).
RIGI occurs at a high frequency. In our GM10115 cell system, Limoli et al. (33,34) observed instability at a frequency of 3% per Gray for X-rays (33) and 4% after high linear energy transfer radiation (34). Similarly, Kadhim et al. (35) found chromosomal changes in 40–60% of cells surviving exposure to alpha-particle concentration at 1 hit/cell. Because the frequency is much higher than observed frequencies of nuclear gene mutations at similar doses, it is unlikely a gene or a gene family is solely responsible for initiating instability. In addition, these chromosomal rearrangements can occur over prolonged periods after the initial radiation exposure. While the phenotypes of instability are well characterized, the cause(s) of the high frequency of initiation and perpetuation remain a mystery. DNA lesions including double-strand breaks have been eliminated as possible causes (36), but changes in methylation patterns (37,38), disruptions to cellular homeostasis (39,40), and/or changes in gene expression have been implicated in the perpetuation of the unstable phenotype (41). Snyder and Morgan (42,43) investigated potential relationships between gene expression changes and instability using gene expression microarray analysis, but no clear associations between a given gene and the unstable phenotype were found.
A role for oxidative stress in RIGI
Persistently elevated levels of free radicals are found in association with RIGI. Clutton et al. (1) and Limoli et al. (3,4) described high levels of free radicals and evidence of free-radical mediated damage associated with RIGI in different assay systems. Further correlation is evidenced in studies where chronic hydrogen peroxide or glucose oxidase exposure each initiated instability (2,44). Correspondingly, antioxidant treatment, and reducing oxygen tension after cellular irradiation each reduced delayed chromosomal alterations (6,7). Administration of free-radical scavengers, to the GM10115 cell system before irradiation, decreased the incidence of instability (5). These studies suggest a role for oxidative stress in perpetuating RIGI. The persistence of oxidative stress in our unstable cells months and years after the initial insult suggests continuous generation of ROS as free radicals generally tend to be short lived (45).
Oxidative stress arises from an imbalance between free-radical production and the capability of opposing antioxidant forces. While ROS can be involved in beneficial processes, for example, by acting as second messengers in signal transduction pathways (46), oxidative stress can perturb several cellular processes of which a combination may be disrupted in concert to destabilize the genome. On a basic level, ROS induces direct damage to cellular structures that may ultimately have carcinogenic potential, e.g. DNA strand breaks, base modifications and DNA–protein cross linkages (47). Furthermore, DNA repair mechanisms, such as mismatch repair, are disrupted by ROS-mediated modifications to crucial repair proteins (48). In addition to direct damage of cellular components, ROS alters global processes thought to contribute to carcinogenesis such as DNA methylation or cell–cell communication through gap junction modification (49). ROS-mediated activation of signaling pathways may also be involved in genome destabilization. After exposure to a mutagen such as N-Methyl-N'-Nitro-N-Nitrosoguanidine or irradiation, signaling pathways involving nuclear factor kappa beta (NF-
B) and activator-protein 1 (AP1) through an ROS-mediated mechanism can increase ERK 1/2 and p38 kinase activities ultimately increasing malignancy potential (50). NF-B and AP1 are involved in cellular proliferation whereas bypassing cellular mitotic checkpoints with unrepaired DNA lesions may increase carcinogenic potential (49). Oxidative stress can affect multiple cellular pathways and processes, and it is unclear which one or combination of these processes is involved genomic destabilization in RIGI. However, in a recent review, Spitz and colleagues (51) presented the intriguing concept of stress response biology that links metabolic oxidation/reduction reactions and cellular responses to ionizing radiation.
In addition to the ambiguity of how oxidative stress perpetuates genomic instability, the source of these ROS is also unclear. ROS, such as the hydroxyl radical or superoxide anion, are naturally generated by several cellular sources: peroxisomes, mitochondria, plasma membrane proteins including NADPH oxidase, and cytosolic enzymatic reactions such as those involving cyclooxygenases (52). Exogenous agents such as cytokines and chemical and physical carcinogens can also increase levels of ROS (53). Because free radicals contain an unpaired electron, they are extremely reactive, short lived, and can modify DNA, proteins and lipids (54). The hydroxyl radical is by far the most reactive and is created either by radiation-mediated cleavage of a water molecule or through the Fenton reaction involving hydrogen peroxide and an iron or copper atom (45). The superoxide radical can be created through a variety of enzymatic reactions but is most commonly a toxic byproduct of mitochondrial respiration. Because mitochondria are major cellular sources of ROS and in particular the superoxide radical, attention is now focused on their involvement in the oxidative stress observed in RIGI.
Mitochondrial function and oxidative phosphorylation
Mitochondria are involved in several vital cellular processes: energy production, apoptosis, pyrimidine biosynthesis, fatty acid metabolism and calcium homeostasis. These double membraned organelles exist in multiple copies within each cell. The inner membrane is folded into many cristae that hold the energy providing electron transport chains (55). Mitochondria contain 2–10 copies of mitochondrial DNA (mtDNA) each and most mammalian cells contain hundreds of mitochondria. mtDNA is a 16 kB circular molecule encoding for 13 proteins of the electron transport chain, 22 tRNA and 2 rRNA molecules (56).
Amidst the many functions described for the mitochondria, the most significant is oxidative phosphorylation for the generation of cellular energy (56). The mitochondrial electron transport chain is made up of >80 component proteins that constitute five complexes designated for cellular energy production. The cytoplasmic breakdown of glucose ultimately results in electron passage through each of the complexes I-IV in the mitochondrial inner membrane. Complex IV, cytochrome c oxidase, donates the electrons to oxygen to form water. Electron movement through complexes I, III, and IV enables movement of a hydrogen ion across the inner membrane into the inter-membrane space creating an electrochemical gradient which is harnessed into ATP production by complex V, ATP synthase (57). Ironically, electron transport while sustaining cellular processes by providing ATP also produces a toxic byproduct, the superoxide anion radical, where electrons may ‘leak’ off the complexes and react with oxygen within the mitochondrial matrix. When electron transport is inhibited due to complex inhibitors or mutations, ROS production rate can increase. However, even under normal conditions, the mitochondria contribute 90% of the cellular free-radical production (52).
Mitochondria and especially mtDNA are vulnerable to the free radicals they produce for a number of reasons: (i) mtDNA are located near the inner mitochondrial membrane where the electron transport chain generates free radicals, (ii) mtDNA have no protective histones, and (iii) mitochondria have limited DNA repair capacity. Because mtDNA encode electron chain components, ROS induced mutations may lead to oxidative phosphorylation impairment which may further increase ROS production causing even more mitochondrial and cellular damage (58).
Mitochondrial dysfunction and cancer
Mitochondrial dysfunction and subsequent oxidative stress are suspected to contribute to many diseases and disorders including cancer. Gross mitochondrial changes are seen in association with cancer (59) and oxidative stress caused by respiratory defects through an inhibition of complex IV (60). Mitochondria have long been suspected to have a role in carcinogenesis beginning with Otto von Warburg's hypothesis that cancer cells have impaired respiratory function (reviewed in ref. 61). Furthermore, in non-transformed cells, most cellular ROS production is derived from cytosolic membrane NADPH oxidase, whereas in transformed cells, the increased ROS production was of mitochondrial origin (62). Most tumors including breast, head, lung, stomach, leukemias and lymphomas, show evidence of mtDNA mutations. Affected mtDNA regions include genes encoding respiratory complexes and areas of the mtDNA involved in replication and transcription (58). These mutations potentially impair mitochondrial function leading to increased ROS production, which in turn may lead to chromosomal abnormalities (63). The carcinogenic potential of these mtDNA mutations is highlighted in experiments where a single point mutation in the mtDNA gene MTATP6, a component of ATP synthase, conferred greater tumorigenicity and apoptotic resistance (64). Correspondingly, mouse fibroblasts mutant for complex II had increased superoxide anion levels, oxidatively damaged proteins, and demonstrated elevated levels of apoptosis and tumorigenesis (65).
The mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD), regulates mitochondrial and cellular oxidant status and also has a role in tumor prevention. Ideally situated in the mitochondrial matrix, this enzyme converts a superoxide anion radical into a hydrogen peroxide molecule, which can then diffuse out of the mitochondria. Catalase then converts hydrogen peroxide into a water molecule in the cytoplasm. Abnormal MnSOD activity has been found in cancer cells (66,67) and upregulating protein levels have tumor suppressive effects, one of which is AP1 suppression (68). These results along with effects of dysfunctional electron transport highlight a possible relationship between increased mitochondrial ROS and carcinogenesis.
Mitochondrial dysfunction and RIGI
Recently, there has been evidence that specifically implicates mitochondrial dysfunction in radiation-induced chromosomal instability. Limoli et al. (3) reported increased levels of dysfunctional mitochondria in radiation-induced unstable clones of GM10115 cells after examining mitochondrial membrane potential. Unstable cells showed decreased mitochondrial membrane potential but increased numbers of mitochondria per cell (3). In addition, Samper et al. (69) found an increased incidence of chromosomal rearrangements in murine fibroblasts with decreased MnSOD activity indicating a role for mitochondrial oxidative stress in genomic instability. Liu et al. (70) and Lyng et al. (71) demonstrate mitochondrial involvement in genomic instability through mechanisms of telomere attrition and the bystander effect respectively. Most recently, Spitz et al. (72) determined that mutations in a mitochondrial electron transport chain protein, succinate dehydrogenase, led to oxidative stress and genomic instability.
In unstable clones, LS-12 and Fe10-3, generated in our laboratory by irradiating GM10115 cells with X-rays or iron ions, respectively (32,73), we also see evidence of mitochondrial dysfunction. Mitochondria from unstable cells show decreased respiratory activity with a corresponding decrease in complex IV activity. Through fluorimetric experiments measuring mitochondrial ROS production, we found that mitochondria from unstable cells contributed more hydrogen peroxide than mitochondria of stable cells presumably due to decreased respiratory rates. Differences in ROS production were not due to varying mitochondrial levels as determined by Mitotracker Green FM fluorimetry measurements. Upon examination of mitochondrial antioxidant status, MnSOD activity was decreased in the unstable cells implying a state of mitochondrial oxidative stress (74). Hence, we conclude that mitochondria contribute to the increased levels of ROS and function to perpetuate the oxidative stress observed in our radiation-induced chromosomally unstable cell lines.
We also demonstrate lower levels of transcripts of select mitochondrial genes in unstable clones (Figure 1). It appears that the rate of mitochondrial gene transcription is reduced or that the rate of mtRNA degradation is accelerated in the unstable cell clones as mitochondrial RNA is selectively vulnerable to degradation caused by oxidative stress (75). This is significant because cancer cells demonstrate variability in mtRNA levels, e.g. the expression of mtRNA is elevated in thyroid cancers and malignant melanomas (76,77), whereas expression levels are abnormally low in glioblastoma cells (78) and renal carcinomas (79). Mitochondrial DNA is also susceptible to free-radical-mediated damage particularly in the transcription regulatory region, the D-loop, as evidenced in tumor cells where D-loop mutations are a frequent event (80). The D-loop contains the replication origin and the two transcription promoters for all mitochondrial genes, and consequently, mutations in this area may lead to decreased gene expression or mitochondrial DNA replication (81). Although in our system, there were no significant differences in mtDNA levels between stable and unstable clones (74), but this does not exclude the possibility of D-loop mutations and/or decreased mitochondrial gene expression contributing to the unstable phenotype.
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Schematic of the role of mitochondrial dysfunction in chromosomal instability
Figure 2 shows a possible scheme for mitochondrial involvement in perpetuating RIGI. Ionizing radiation has a number of cellular effects some of which are highlighted. ROS levels may be increased through direct hydrolysis of water and ROS can damage electron transport chain proteins that in turn can create more radicals. mtDNA is susceptible to free-radical-mediated damage that may result in dysfunctional proteins that can lead to electron transport dysfunction generating more free-radical production as electrons cannot complete the chain and react with molecular oxygen. Another possibility is that ionizing radiation may damage mtDNA directly. High levels of ROS are then perpetuated by successive cycles of cytokine induction stimulating ROS production in turn stimulating cytokine induction. Radiation can also induce the production of cytokines that not only increase ROS levels but are also upregulated by increased ROS levels.
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A precedence for the cytokine–ROS–cytokine cycle was proposed by Iyer and Lehnert (82
) and later revisited by Morgan et al. (83). In this model, radiation exposure increased cytokine production, e.g. transforming growth factor ß (TGFß) levels, which stimulated ROS production through a membrane NADPH oxidase. Increased levels of ROS further increased TGFß levels in the media perpetuating this cycle over time (82). Recently Yoon et al. (80) found that during a TGFß mediated senescent arrest, TGFß induced a prolonged increase in ROS levels through decreased activity of mitochondrial complex IV. Cytokines have also been found to affect methylation patterns that inhibit DNA repair (84), which may further aggravate the instability. Thus, cytokines exert multiple cellular effects that may upregulate ROS and together with ROS generated after mitochondrial dysfunction cause genome destabilization after irradiation. |
Conclusions |
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The perpetuation of instability over generations requires a heritable element or an event that can be passed onto the progeny. Since a single gene mutation is not a likely cause because of the high frequency of instability, oxidative stress is an attractive mechanism exerting broad effects that could disrupt cellular processes maintaining genomic integrity. We hypothesize a combination of events including mitochondrial dysfunction contribute to perpetuate oxidative stress which provides a source of damage for generating the chromosomal rearrangements perpetuated over time as RIGI.
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Acknowledgments |
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We thank Drs Andrew Snyder, Paul Shapiro and Dan Schulze for their critical reading of this manuscript. This work was supported by the Office of Science's Biological and Environmental Research Program (BER), U.S. Department of Energy, Grant No. DE-FG02-01-ER63230 and National Institutes of Health Awards CA73924 and CA83872.
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Notes |
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*To whom correspondence should be addressed at: Radiation Oncology Research Laboratory, University of Maryland School of Medicine, 655 West Baltimore Street, BRB 7-009 Baltimore, MD 21201-1559, USA. Tel: +1 410 706 1572; Fax: +1 410 706 6138; Email: gkim002{at}umaryland.edu
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Received on August 26, 2006; revised on September 7, 2006; accepted on September 15, 2006.
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