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1. Introduction
Each mitochondrion consists of 16,569 base pairs which encodes 37 genes, all of which are essential for normal mitochondrial function (Anderson et al., 1981). Each human cell contains several hundred copies of mitochondrial DNA, encoding 13 genes that are required for oxidative phosphorylation, 22 transfer RNAs and 2 ribosomal RNAs (Anderson et al., 1981). Mitochondria are vital organelles, which generate the majority of the cells energy through oxidative phosphorylation (Wallace, 2005). During this process, reactive oxygen species (ROS) are produced, that can leak out and react with a range of cellular components, including the mitochondrial genome (Richter et al., 1988). Therefore, it has been suggested that levels of oxidative DNA damage are higher in mitochondrial DNA than in nuclear DNA, with mitochondrial DNA accumulating mutations at a 10- to 50- fold higher rate (Hudson et al., 1998; Michikawa et al., 1999; Pakendorf and Stoneking, 2005; Yakes and Van Houten, 1997). If this mitochondrial DNA damage is not repaired, it can lead to disruption of the electron transport chain and increased generation of ROS, possibly resulting in vicious cycle of ROS production and mitochondrial DNA damage, leading to energy depletion and ultimately cell death (Harman, 1972; Miquel et al., 1980). Therefore suggesting that mitochondria must employ some form of repair or defence mechanism against such forms of deleterious damage.
The integrity of mitochondrial DNA repair plays a central role in maintaining homeostasis in the cell and thus the efficient repair of mitochondrial DNA damage serves as an essential function in cellular survival. In comparison to nuclear DNA repair, our knowledge regarding mitochondrial DNA repair is limited. In fact, it was originally believed that mitochondria employed no repair mechanisms and damaged DNA was not repaired, but was merely degraded. This was primarily based on a study published in 1974, which demonstrated the inability of mitochondria to remove cyclobutyl pyrimidine dimers after exposure to ultraviolet light (Clayton et al., 1974). This theory remained for many years, but now it is abundantly clear that multiple DNA repair pathways and the controlled degradation of mitochondrial DNA, work together to maintain the integrity of the mitochondrial genome (Berneburg et al., 2006; Liu and Demple, 2010). Initially the repair of most mitochondrial DNA damage was thought to be limited to short-patch base excision repair (BER) (Stierum et al., 1999). However, the complex range of DNA lesions inflicted on mitochondrial DNA by ROS and potential replication errors indicated that such a restricted repair mechanism would be insufficient. Our knowledge of mitochondrial DNA repair has recently witnessed a rapid expansion and it is now evident that mitochondria also employ long-patch BER (Akbari et al., 2008; Liu et al., 2008; Szczesny et al., 2008; Zheng et al., 2008), mismatch repair (de Souza-Pinto et al., 2009; Mason et al., 2003), homologous recombination and non-homologous end-joining (Bacman et al., 2009; Fukui and Moraes, 2009; Thyagarajan et al., 1996). In addition, sanitation of the mitochondrial deoxynucleotide triphosphate (dNTP) pool and selective degradation of heavily damaged mitochondrial DNA play important roles in maintaining mitochondrial DNA integrity and preventing cell death (Bacman et al., 2009; Ichikawa et al., 2008; Shokolenko et al., 2009). The majority of the proteins dedicated to DNA repair have to be transcribed and translated from nuclear DNA where they are encoded and imported into the mitochondrion (Bohr, 2002).
Our DNA, both nuclear and mitochondrial, is constantly exposed to endogenous and exogenous agents that induce DNA lesions and genomic instability (De Bont and van Larebeke, 2004; Sander et al., 2005). In the absence of DNA repair, the genome would be unable to survive the multitude of lesions that form throughout the cell cycle. Therefore, a range of molecular mechanisms has evolved that ensures that damaged DNA is effectively repaired. These pathways coordinate the repair of DNA lesions and the stalling of the cell cycle to allow repair to occur (Harper and Elledge, 2007). DNA repair mechanisms have been extensively studied in the nucleus and increasing data demonstrates how distinct DNA lesions are repaired by different DNA repair pathways including homologous recombination, non-homologous end joining, base excision repair, nucleotide excision repair, mismatch repair, and translesion synthesis (Hoeijmakers, 2009). The relevance of the DNA repair pathways in the maintenance of genome integrity and cellular survival is evidenced by the critical consequences in the survival of organisms when deficiencies in key enzymes of the DNA repair pathways occur (Martin et al., 2008).
In contrast to the repertoire of nuclear DNA repair pathways, for many years, the repair of mitochondrial DNA damage was thought to be limited to short-patch BER (Stierum et al., 1999). However more recently with increasing knowledge of the likely array of lesions inflicted on mitochondrial DNA, it was suggested that such a limited repair repertoire would be insufficient. Studies have identified an expanded range of mitochondrial DNA repair processes including long-patch base excision repair, mismatch repair, homologous recombination and nonhomologous end-joining (Boesch et al., 2011; Liu and Demple, 2010; Yang et al., 2008). It is still generally considered that there is no nucleotide excision repair (NER) in the mitochondria. However, it has been shown that the NER gene, Cockayne syndrome B (CSB) is involved in the removal of oxidative DNA damage from the nucleus, such that CSB-deficient cells demonstrated reduced repair rates of 8-oxoG DNA lesions and extracts from CSB-deficient cells fail to incise oligonucleotides containing 8-oxoG (Balajee et al., 1999) (Dianov et al., 1999; Le Page et al., 2000; Selzer et al., 2002). CSB has also been shown to act in concert with OGG1 in the repair of these lesions (Tuo et al., 2002; Tuo et al., 2001). Due to the generation of ROS in the mitochondria and the increased levels of oxidative damage it was hypothesized that mitochondria-targeted CSB could have a role in repair of mitochondrial DNA. To this end, Stevnsner et al. demonstrated that CSB-deficient cells exhibited a reduced ability to repair 8-oxoG in the mitochondria, suggesting possible NER activity (Stevnsner et al., 2002a). Similarly, the presence of translesion synthesis (TLS) in mitochondria has not been fully elucidated. In the nucleus, TLS is carried out by specialized polymerases, which have the ability to copy defective DNA templates. The possibility of mitochondrial TLS has been suggested due to the fact that the mitochondrial polymerase POLG is capable of mutagenic bypass through DNA lesions introducing dA opposite an AP site or an 8-oxodG (Graziewicz et al., 2007; Pinz et al., 1995) and also opposite benzo[a]pyrene and benzo[c]phenanthrene diol epoxide adducts of deoxyguanosine and deoxyadenosine (Graziewicz et al., 2004). To date, the presence of TLS activity in vivo in mitochondria remains to be shown. For both NER and TLS, further research is necessary to define the precise mechanisms of these processes in the mitochondria.
2.1. Base excision repair
The mitochondrial DNA sits on the inner side of the mitochondrial inner membrane, where most reactive oxygen species (ROS) are generated, rendering it highly susceptible to oxidative damage. BER is one of the main pathways for the repair of oxidized modifications both in nuclear and mitochondrial DNA (Slupphaug et al., 2003). As mentioned above, previously the repair of mitochondrial DNA damage and in particular oxidative DNA damage was thought to be limited to short-patch BER (Stierum et al., 1999), which replaces a single nucleotide by the sequential action of DNA glycosylases, an apurinic/apyrimidinic (AP) endonuclease, a DNA polymerase, an abasic lyase activity and DNA ligase (Dianov et al., 2001)(Figure 1). In addition to oxidative DNA damage, BER is the primary pathway required for repair of small DNA modifications induced by alkylaltion and deamination. As in nuclear BER, mitochondrial BER is initiated with recognition of the modified base and its removal is followed by processing of the apurinic/apyrimidinic (AP) site, incorporation of the correct nucleotide and finally strand ligation (Chan et al., 2006; Dianov et al., 2001). A schematic representation of the BER pathway in mitochondria is illustrated in Figure 1.
The 1st step of BER is initiated by DNA glycosylases, which recognize the modified base and cleave the N-glycosidic bond, resulting in an abasic site. It has been shown that a number of glycosylases are bi-functional DNA glycosylases such that they also have AP lyase activity, which enables the cleavage of the DNA backbone (Robertson et al., 2009). Mitochondrial and nuclear glycosylases are encoded by the same nuclear gene, however isoforms are generated by alternative transcription initiation sites and alternative splicing (Bohr, 2002; Nilsen et al., 1997).
Figure 1.
Schematic representation of the BER pathway in mitochondria.
The mitochondrial DNA glycosylases include the 8-oxoguanine DNA glycosylase-1 (OGG1), the uracil DNA glycosylase (UNG), MYH, endonuclease III homolog (NTH1) and the NEIL glycosylases. OGG1 is a bi-functional glycosylase that is required for the recognition and cleavage of 8-hydroxy-guanine (8-oxoG) oxidative DNA lesions from double-stranded DNA (Kuznetsov et al., 2005). UNG was the 1st glycosylase to be identified and is involved in the removal of uracil from DNA, generated by deamination of cytosine or by misincorporation of dUMP (Lindahl, 1974). The removal of uracil is vital, because of its ability to pair with adenine resulting in GC to AT transition mutations upon replication (Darwanto et al., 2009). MYH is involved in the removal of adenine misinserted opposite 8-oxoG (Takao et al., 1999). NTH1 is also involved in the removal of oxidized DNA lesions (Takao et al., 2002). The NEIL glycosylases are responsible for excising oxidative DNA lesions such as 2,6-diamino-5-foramidopyrimidine (FapyG) and 4,6-diamino-5-formamidopyrimidine (FapyA) (Doublie et al., 2004). There are three main isoforms, NEIL1, NEIL2 and NEIL3, which are present in both the nucleus and the mitochondria (Gredilla et al., 2010b; Hazra et al., 2002a; Hazra et al., 2002b). Whilst partial redundancy has been described for these glycosylases, NEIL1 knock-out mice accumulate mitochondrial DNA deletions to a greater extent than wild-type mice and also develop symptoms associated with metabolic syndrome (Vartanian et al., 2006).
After recognition and cleavage of the modified base by the specific DNA glycosylase, an abasic site is formed. The AP endonuclease (APE1) is involved in this step of repair. APE1 cleaves on the immediate 5’ side of the AP site, leaving a 3’ hydroxyl and 5’-deoxyribose-5-phosphate (5’-dRP) residue (Masuda et al., 1998). APE1 is the major endonuclease in mammalian cells in both the nucleus and the mitochondria (Tell et al., 2005). The functional importance of APE1 is highlighted by the findings that knockout mice for the APE1 gene are embryonic lethal at very early stages (6–8 days) suggesting that cell survival is critically compromised in the absence of APE1 (Ludwig et al., 1998; Xanthoudakis et al., 1996). Heterologous expression of APE1 restores resistance to DNA-damaging agents in AP endonuclease-deficient cells (Li et al., 2008). APE1 is the only AP endonuclease in mitochondrion, and loss of mitochondrial APE1, not of the nuclear APE1 (Chattopadhyay et al., 2006), is believed to be responsible for triggering apoptosis, therefore highlighting APE1 as a potential therapeutic target. (Li et al., 2008).
Once the AP site has been processed by APE1, the only known mitochondrial DNA polymerase, POLG is required to insert the correct nucleotide in the generated gap (Ropp and Copeland, 1996). Two different BER pathways exist depending on the number of nucleotides that is incorporated by POLG. Short-patch BER involves the incorporation of one single nucleotide into the gap, while long-patch BER involves the incorporation of several nucleotides, usually in the range of 2 to 7 (Robertson et al., 2009). During the long-patch BER process, this incorporation of multiple nucleotides results in the exposure of the original DNA strand as a single-stranded overhang or a flap structure (Xu et al., 2008). Therefore increasing the complexity of long-patch BER, as additional enzymatic activities are required to process this flap. Increasing evidence suggests that in both the nucleus and the mitochondria, this structure is recognized and cleaved by the flap endonuclease, FEN1 (Kalifa et al., 2009; Klungland and Lindahl, 1997). Although FEN1 is clearly involved in mitochondrial BER, studies have suggested the existence of additional activities involving the enzyme Dna2 can also enable the process. Dna2 was originally identified in yeast as a nuclear DNA helicase with an endonuclease activity required for removing part of an RNA or DNA flap structure (Zheng et al., 2008) and yeast Dna2 has been known for some time to function in the nucleus along with FEN1 to process 5′ flaps (Budd and Campbell, 1997). Significantly, the major isoform of Dna2 is localized to the mitochondria. (Copeland and Longley, 2008; Duxin et al., 2009). Current work implies that mammals have evolved to utilize FEN1 as the only nuclear flap endonuclease, whereas both FEN1 and DNA2 appear to function together in mitochondria (Duxin et al., 2009).
The final process in the mitochondrial BER pathway involves sealing of the nick, which requires the mitochondrial DNA ligase, Ligase III. It was shown to be an ATP independent enzyme, similar to the nuclear DNA ligase (Lakshmipathy and Campbell, 1999b). It is involved in both mitochondrial replication and repair. Recently it has been demonstrated that Ligase III is critical for mitochondrial DNA maintenance and viability, but is dispensable for Xrcc1-mediated nuclear BER (Gao et al., 2011; Simsek et al., 2011). Depletion of DNA ligase III in the mitochondria by antisense DNA ligase III mRNA expression led to a decrease in cellular mitochondrial DNA copy number and increased levels of single-strand DNA breaks within the mitochondrial genome (Lakshmipathy and Campbell, 2001). Ongoing investigations on how the organization of mitochondrial DNA affects BER suggests that mitochondrial DNA association to the inner mitochondrial membrane may be critical for efficient BER (Boesch et al., 2010).
2.2. Mismatch repair
The presence of mismatch repair (MMR) activity in the mitochondria is a controversial area. In 2003, Mason et al. demonstrated that mitochondrial extracts from rat liver exhibited a low but significant MMR activity and that this activity was independent, of one of the main nuclear MMR proteins, MSH2 (Mason et al., 2003). Therefore suggesting that the mitochondrial MMR pathway may be distinct from nuclear MMR. To date, data suggesting the presence of the nuclear MMR proteins in the mitochondria has been conflicting. In 2009, de Souza-Pinto et al. detected the classical MMR proteins MSH3, MSH6 and MLH1 in the nuclei but not in mitochondria (de Souza-Pinto et al., 2009). However we and others, have detected the presence of MLH1, but not MSH2, in the mitochondria of human tumor cells and mouse liver, respectively (Martin et al., 2010; Mootha et al., 2003). Furthermore, our recent data suggests a role for MLH1 in mitochondrial oxidative DNA repair, such that MLH1 deficiency in combination with silencing of the mitochondrial genes, POLG and PINK1, amongst others results in an accumulation in mitochondrial 8-oxoG lesions, incompatible with cell viability (Martin et al., 2011; Martin et al., 2010). Studies have also suggested that mitochondrial DNA mismatch-binding activity is due to the Y-box-binding protein, YB-1 (de Souza-Pinto et al., 2009). Mitochondrial extracts depleted of YB-1 demonstrated a significantly reduced mismatch-binding and repair activity and also a reduced rate of cellular respiration, suggestive of mitochondrial dysfunction. Significantly, silencing of YB-1 by RNA interference (RNAi) also resulted in increased mitochondrial DNA mutagenesis, therefore suggesting that mitochondria do have a MMR pathway, which involves YB-1. The YB-1 mediated mitochondrial mismatch-binding activity was shown to have no bias in favor of the matrix strand and is therefore prone to the introduction of mutations. Recent data has suggested that it can specifically recognize and bind base mismatches and small insertion/deletion loops. In S. cerevisiae, Msh1 which is a homologue of the bacterial MutS component, can repair G:A mispairs in mitochondrial DNA, which are generated by replication past 8-oxodG, as well as other mismatches (Chi and Kolodner, 1994). Msh1 is also thought to be involved in mitochondrial DNA recombination, which may help prevent oxidative lesion-induced instability of the mitochondrial genome (Dzierzbicki et al., 2004; Kaniak et al., 2009; Mookerjee et al., 2005). To date the full extent of mismatch repair activity in mammalian mitochondria remains to be elucidated. BER may also be involved in repairing mitochondrial mismatches and therefore it is possible that proteins that participate in mitochondrial BER may have a role in the downstream activities of the mitochondrial MMR pathway.
2.3. Homologous recombination
Double-strand breaks (DSBs) represent one of the most lethal forms of DNA damage. In the nucleus, even one DSB can be lethal whilst in contrast because the mitochondria possess multiple copies of wild type mitochondrial DNA, this can compensate resulting in a less critical presence of a DSB. Even so, DSB repair has been identified in the mitochondria. In general, homologous recombination (HR) is the primary mechanism for error-free repair of DSBs. HR also plays a critical role in facilitating replication fork progression when the polymerase complex encounters a blocking DNA lesion. In 1995, Ling et al identified the presence of HR in mitochondria in yeast (Ling et al., 1995). It has also been shown that mitochondria are able to repair DSBs in Chinese hamster ovary cells (Le Doux et al., 1992). Rad51, the central mediator of nuclear HR, Rad51C and XRCC3, have all been shown to localize to the mitochondria in human cells (Sage et al., 2010). Rad51 has been shown to bind mitochondrial DNA following exposure to cells upon oxidative stress. Rad51-mediated activity is necessary for regulating mitochondrial DNA copy number under conditions of oxidative stress and this activity requires the functions of Rad51C and XRCC3. In the nucleus, Rad51 and XRCC3 have been shown to cooperate in regulating replication fork progression on damaged chromosomes, therefore it has been suggested that mitochondrial Rad51, Rad51C and XRCC3 ensure faithful completion of mitochondrial DNA replication as the fork encounters blocking lesions. In addition, a study by Thyagarajan et al., have demonstrated that human mitochondrial extracts have the ability to catalyze HR of different DNA substrates (Thyagarajan et al., 1996). Further evidence of mitochondrial HR analyzed segregated mitochondrial DNA mutations in a heteroplasmic mitochondrial DNA population and identified combinations of these two mutations in different mitochondrial DNA molecules indicating HR and crossing over events between mitochondrial DNA molecules with segregated mutations (Zsurka et al., 2004). BRCA1, the breast and ovarian cancer susceptibility gene, which plays a role in the HR pathway, has also been shown to localize to the mitochondria and was found to colocalize with mitochondrial DNA clusters (Coene et al., 2005).
2.4. Non-homologous end joining
Studies have shown that mitochondrial protein extracts possess non-homologous end-joining (NHEJ) activity. NHEJ is highly precise in the case of DNA with cohesive ends while blunt-ended DNA are rejoined with less efficiency and precision (Roth et al., 1985). In mitochondrial extracts, it has been demonstrated that both cohesive and blunt-ended DNA substrates can be rejoined, although the latter with much lower efficiency (Lakshmipathy and Campbell, 1999a). Irrespective of which DNA substrate was used, the majority of recovered products were precisely repaired. Analysis of imprecisely repaired products revealed the presence of deletions that spanned direct repeat sequences. These deletions were similar to those observed in the mitochondrial DNA of certain pathological states as well as in aging cells. Ku80 is required for nuclear NHEJ due to its DNA end-joining activity. Mammalian mitochondrial DNA end-joining activity was reported to be practically indistinguishable from that of the nuclear activity. This observation led to the investigation and subsequent demonstration that Ku80 is also required for mammalian mitochondrial DNA end-joining activity (Feldmann et al., 2000).
The possibility of mitochondrial degradation was first proposed because of early studies suggesting that UV-induced pyrimidine dimmers were not repaired in mammalian mitochondria (Clayton et al., 1974). Furthermore, in response to treatment with mutagenic agents such as ethylmethane sulfonate, N-methyl-N’-nitrosoguanidine and benzo(a)pyrene, mitochondrial DNA from HeLa cells only accumulated few mutations suggesting that mitochondrial DNA accumulating excessive amounts of damage or irreparable lesions, is not replicated (Mita et al., 1988). More recently, further investigation into this process has revealed that extensive or persistent DSBs result in mitochondrial DNA degradation (Alexeyev et al., 2008; Bacman et al., 2009; Fukui and Moraes, 2009). Such that the signal that triggers mitochondrial DNA degradation has been attributed to DSBs, generated by stalled DNA or RNA polymerases on the damaged mitochondrial DNA template. Degradation of these molecules prevents mutagenesis and maintains mitochondrial DNA integrity. In the case of UV-induced pyrimidine dimers and benzo(a)pyrene-induced adducts, the stalled RNA or DNA polymerase would trigger the degradation process. More recently, studies have suggested that oxidative stress can lead to the degradation of mitochondrial DNA and that strand breaks and abasic sites prevail over mutagenic base lesions in ROS-damaged mitochondrial DNA (Shokolenko et al., 2009). Furthermore, inhibition of abasic site processing by APE1 and inhibition of BER by methoxyamine treatment enhanced this degradation in response to oxidative damage, suggesting that the inability to repair mitochondrial DNA damage may be the signal for its degradation (Shokolenko et al., 2009). The elimination of damaged mitochondrial DNA was preceded by the accumulation of linear mitochondrial DNA molecules, which potentially represent degradation intermediates. These intermediates, unlike undamaged circular mitochondrial DNA molecules, are susceptible to exonucleolitic degradation thus ensuring the specificity of the process. Therefore supporting the observation by Suter and Richter who demonstrated that 8-oxoG content of circular mitochondrial DNA is low and does not increase in response to oxidative insult in contrast to fragmented mitochondrial DNA which had very high 8-oxoG content, that further increased after oxidative stress (Suter and Richter, 1999).
3.1. Mitochondrial DNA degradation nuclease
The Endonuclease G (EndoG) was initially proposed to be the nuclease responsible for selectively degrading non-replicable mitochondrial DNA. Such that Ikeda and Ozaki showed that mitochondrial EndoG is more active in vitro on oxidatively modified DNA compared to undamaged DNA suggesting that it may be involved in the degradation of oxidatively damaged mitochondrial DNA (Ikeda and Ozaki, 1997). However, more recent studies illustrated that EndoG-deficient cells or EndoG null mice showed no accumulation in mitochondria DNA mutation rate or defects in mitochondrial structure, therefore suggesting that EndoG may not be the exclusive nuclease involved (Irvine et al., 2005). Davies et al. reported that upon removal of EndoG activity from the mitochondria, another nuclease activity can be detected internal to the inner mitochondrial membrane (Davies et al., 2003). This exonuclease causes a gradual degradation of amplified DNA and linearized pBR322 plasmid DNA without the site-specific cleavage seen with EndoG. However they also showed that when supercoiled mitochondrial DNA is used as a substrate, both endo- and exonuclease activities could be detected. Whether the endo- and exonucleolytic activities arise from the same nuclease or from separate enzymes remains under investigation.
4. Sanitation of the mitochondrial deoxynucleotide triphosphate pool
So far, we have only discussed repair and damage of mitochondrial DNA, however the free deoxynucleotide triphosphate (dNTP) pool is also exposed to oxidation and other stresses. dNTPs are the precursors used by DNA polymerases for replication and repair of nuclear and mitochondrial DNA. The cell employs specialized enzymes that remove for example, oxidized dNTPs that otherwise may be incorrectly incorporated during DNA synthesis such as 8-oxo-2’-deoxyguanosine triphosphate (8-oxo-dGTP). 8-oxo-dGTP can be potentially incorporated opposite A by POLG, resulting in 8-oxodG:dA base pairs which are resistant to the proof-reading activity of POLG, ultimately resulting in AT to CG transversions (Hanes et al., 2006; Pursell et al., 2008). As a defense to such activities, MUTYH, present in both the nucleus and mitochondria, has the ability to remove the misincorporated adenine, enabling insertion of dCMP and removal of the 8-oxoguanine by BER (Takao et al., 1999; van Loon and Hubscher, 2009). Oxidation of the mitochondrial dNTP pool represents a significant threat to mitochondrial DNA integrity with the 8-oxo-dGTP concentrations in mitochondrial extracts from rat tissues ranging from 1-10% of the total dGTP (Pursell et al., 2008).
The major defense mechanisms against 8-oxo-dGTP, is its elimination from the dNTP pool by the mitochondrial MTH1 (Kang et al., 1995; Nakabeppu, 2001). MTH1 can hydrolyze 8-oxodGTP to 8-oxodGMP, which is not a substrate for DNA polymerases and therefore would not be incorporated into the DNA. MTH1 can also hydrolyze, 8-oxo-2’-deoxyadenosine triphosphate and 2-hydroxy-2’-deoxtadenosine triphosphate to the monophosphates (Sakai et al., 2002). 8-oxoG accumulation in mitochondrial DNA was observed in MTH1-null mouse embryonic fibroblasts following hydrogen peroxide treatment and in dopaminergic neurons from MTH1-null mice following 1-methyl-4-phenyl-1,2,3,6,-tetreadropyridine treatment (Yamaguchi et al., 2006; Yoshimura et al., 2003). MTH1 was also shown to protect cells from the cytotoxicity of sodium nitoprusside by preventing 8-oxoG accumulation in mitochondrial DNA (Ichikawa et al., 2008). Taken together, this strongly suggests that MTH1 plays a critical role in protecting mitochondrial DNA from oxidized dNTPs.
The DUT gene, which encodes a UTPase which can remove dUTP from the nucleotide pool, also encodes an alternative splice variant that is located to mitochondria (Ladner and Caradonna, 1997). dUTP can arise from deamination of dTTP. The mitochondrial protein is 23 kDa and is constitutively expressed, in contrast to the nuclear isoform, which is cell cycle regulated. If modified dNTPs are incorporated into mitochondrial DNA they must be removed via the BER pathway, which can repair modifications of single nucleotides already incorporated in DNA.
Accumulating data increasingly shows the involvement of various mitochondrial DNA mutations in human diseases. Several disorders such as myopathy, optic atrophy and Leigh syndrome arise as a result of mitochondrial alterations (Edmond, 2009). In addition, a number of pathologies are also caused by mutations in nuclear genes that encode for mitochondrial proteins (Chan and Copeland, 2009; Horvath et al., 2009; Tuppen et al., 2010). The most common genetic defect seen in individuals with mitochondrial DNA-associated disease are deletions (Holt et al., 1988; Shoffner et al., 1989) or point mutations (Goto et al., 1990; Wallace et al., 1988). Mitochondrial DNA deletions have been shown to be important in pathogenesis in a number of ways. Single mitochondrial DNA deletions are a common cause of sporadic mitochondrial disease and an identical mitochondrial DNA deletion is present in all cells of the affected tissue (Schaefer et al., 2008). Some individuals with mitochondrial disease have multiple mitochondrial DNA deletions in the affected tissues, usually the muscle and the central nervous system (Taylor and Turnbull, 2005). These involve nuclear genes encoding proteins involved in either mitochondrial nucleotide metabolism or mitochondrial DNA maintenance. There are also a number of reports of mitochondrial deletions in aged post-mitotic tissues and individuals with neurodegenerative disease (Bender et al., 2006; Kraytsberg et al., 2006; Taylor and Turnbull, 2005). These pathogenic mitochondrial DNA deletions have been suggested to be as a result of mitochondrial DNA repair. It has been postulated that mitochondrial deletions are initiated by single-stranded regions of mitochondrial DNA generated through exonuclease activity at DSBs (Krishnan et al., 2008). Ultimately, these single strands are free to anneal with microhomologous sequences such as repeat sequences on other single-stranded mitochondrial DNA or within the noncoding region (Haber, 2000). Once annealed, subsequent repair, ligation and degradation of the remaining exposed single strands would result in the formation of an intact mitochondrial genome harboring a deleted portion.
5.1. Mitochondrial DNA repair and neurodegenerative disease
Mitochondrial DNA damage is found in affected neurons in the majority of neurodegenerative disorders, and is often associated with oxidative DNA damage and mitochondrial dysfunction (de Moura et al., 2010). Accumulation of nuclear DNA and mitochondrial DNA lesions has been demonstrated to be a critical factor contributing to genomic instability and mitochondrial dysfunction in neurodegenerative diseases (Lin and Beal, 2006; Yang et al., 2008). DNA repair mechanisms are essential for the proper maintenance of the mammalian central nervous system. Therefore, deficiency in DNA repair, particularly in BER, is increasingly recognized as a major contributor to neuronal loss. Neurodegenerative diseases are increasingly associated with mutations in mitochondrial DNA strongly suggesting that neurons are particularly sensitive to mitochondrial dysfunction. Neurons in both the peripheral and central nervous systems are adversely affected by mitochondrial mutations (Wallace, 2001). Examples of neurodegenerative diseases associated with mitochondrial DNA damage and repair (Finsterer, 2006; Servidei, 2004) include but are not limited to: Alzheimers disease, Parkinsons disease and Huntingtons disease. The fact that many of these share similar neuropathological features with multiple neurodegenerative disorders, suggests a significant role for mitochondrial dysfunction in the pathogenesis of neurodegenerative disorders.
Alzheimers Disease, the most common form of age-associated dementia, is a progressive and always fatal disorder characterized clinically by memory loss and behavioral abnormalities, and histopathologically by deposition of amyloid β-peptide (Aβ), cytoskeletal pathology, degeneration of synapses and neuronal death (Mattson, 2004). Several studies have shown that oxidative modification to both nuclear DNA and mitochondrial DNA are increased in brains of Alzheimers disease patients (Gabbita et al., 1998; Mecocci et al., 1994; Wang et al., 2005). An accumulation of 8-hydroxy-2-deoxyguanosine (8-OHdG) was observed in mitochondrial DNA isolated from cortical brain regions of Alzheimers patients (Mecocci et al., 1994). Furthermore significant BER dysfunction was observed in brains of Alzheimers patients, resulting from reduced UDG, OGG1 and POLB activities (Weissman et al., 2007). Parkinson's disease is the second most prevalent neurodegenerative disease, affecting approximately 2% of individuals over the age of 65 years (de Rijk et al., 1997; Mouradian, 2002). It is clinically characterized by resting tremor, postural instability, gait disturbance, bradykinesia and rigidity. Increasing evidence suggests that oxidative damage to DNA, both nuclear and mitochondrial, contributes to the degeneration of dopaminergic neurons in Parkinsons disease (Alam et al., 1997). Swerdlow et al. demonstrated that mitochondria from Parkinsons patients exhibit increased production of ROS, decreased activity of complex I and increased DNA damage (Swerdlow et al., 1996). Huntington's disease is a dominantly inherited neurodegenerative disorder caused by expanded CAG trinucleotide repeats in the amino-terminal coding region of the huntingtin (Htt) gene (Cepeda et al., 2007). It was suggested that expansion of the CAG trinucleotide repeats in Huntingtons disease requires DNA break repair and involves several DNA repair enzymes including FEN1 (Lee and Park, 2002; Spiro et al., 1999). It was also proposed that faulty processing of strand breaks by FEN-1, initiates CAG repeat instability in mammalian cells (Spiro and McMurray, 2003). It was recently demonstrated that the accumulation of oxidative DNA lesions in brains and livers of Huntingtons mice, including 8-oxoG, 5-hydroxyuracil (5-OHU), 5-hydroxycytosine (5-OHC), and formamidopyrimidine (FAPY), were correlated with the degree of trinucleotide expansion, suggesting that that initiation of CAG repeats may occur during removal of oxidative DNA lesions, and could be specifically associated with OGG1 activity (Kovtun et al., 2007).
5.2. Mitochondrial DNA repair and cancer
The extent to which cancer is caused by or is a consequence of mitochondrial genomic alterations is unknown, but substantial data suggest an involvement of mutations in mitochondrial DNA in the carcinogenic process. Mitochondrial defects have long been suspected to play an important role in the development and progression of cancer (Carew and Huang, 2002; Hockenbery, 2002; Warburg, 1956). However the majority of the existing data currently show an association of increased mitochondrial DNA mutations in different tumours with only little direct evidence for a functional role of these mutations. Tumour cells, in general, have increased levels of mitochondrial DNA transcripts, while both increases and decreases in the levels of tumour cell mitochondrial DNA have been reported.
Data suggesting a role for mitochondrial DNA in cancer regression comes from studies with the chemotherapy drugs, bis-2-chloroethylnitrosourea (BCNU) and temozolomide. These drugs induce cell death by alkylation of DNA bases to form mutagenic O6 methylguanine and interstrand cross-links (Ludlum, 1997; Newlands et al., 1997). The repair enzyme O6methyloguanine DNA methyltransferase (MGMT) removes O6methylguanine DNA damage (Bobola et al., 1995; Bobola et al., 1996). Studies have shown that transfecting haematopoietic cell lines with low repair activity for alkylated DNA damage with mitochondrial-targeted and nuclear-targeted MGMT generated resistance against the cytotoxic effects of BCNU and temozolomide (Cai et al., 2005). Significantly, this effect was more dependent on mitochondrial MGMT in comparison to the nuclear MGMT suggesting the contribution of mitochondrial DNA repair in the generation of drug-resistant tumour cells.
Many theories have been proposed to explain the phenomenon of aging (Kirkwood, 2005). Amongst these is the mitochondrial free radical theory of aging, which states that the accumulation of mitochondrial damage and the progressive accumulation of free radical damage in post-mitotic tissues, is the cause of aging (Harman, 1956). Because mitochondria are the main generators of ROS and consequently the main target of their DNA damaging effects, oxidative damage can result in increasing rates of mitochondrial DNA mutations. A vicious cycle can potentially occur as mitochondria encode for components of the respiratory chain and ATP synthase complexes, therefore mutations in the mitochondrial DNA may cause defects in oxidative phosphorylation resulting in an increased generation of ROS and further mitochondrial DNA damage (Miquel et al., 1980).
The mitochondrial theory of ageing has been controversial, with numerous studies performed to elucidate the precise correlation between oxidative damage, mitochondrial mutations and aging. One prominent study involves the generation of a mouse model that illustrates an increase in mitochondrial DNA mutation and oxidative phosphorylation defects. This mouse model which carries an error-prone form of POLG was generated, and correlated with decreased life expectancy and a premature ageing phenotype (Kujoth et al., 2005; Trifunovic et al., 2004). However there was little evidence of increased ROS or oxidative damage as a result of the mitochondrial DNA replication errors, suggesting the lack of the previously proposed “vicious cycle”. Studies of the various tissues of these mice, have suggested that it is the accumulation of mitochondrial DNA deletions and clonal expansion identified in the brain and heart that drive the premature aging phenotype (Vermulst et al., 2007)(Vermulst et al., 2008). More recently, an alternative study has now suggested that it is random point mutations occurring in mitochondrial DNA analyzed in the liver and heart that are the driving force behind the aging phenotype (Edgar et al., 2009). The discrepancies between the studies may be due to the analysis of either mitotic or post-mitotic tissues. Such that, it has been suggested that in post-mitotic tissues, mitochondrial DNA deletions occur initially during repair of damaged DNA whilst in mitotic tissues it is thought that mitochondrial DNA point mutations are likely to be generated during replication (Reeve et al., 2009).
A number of studies suggest that although oxidative damage of mitochondrial DNA does accumulate with age in mammalian cells, this accumulation does not regulate lifespan (Arnheim and Cortopassi, 1992; Barja and Herrero, 2000). Similarly, in Drosophila, mitochondrial ROS production increases with age but does not influence its lifespan (Sanz et al., 2010). One reason has been postulated such that scavenging free radicals could increase life expectancy whilst increasing ROS may lead to premature cell death. To address this several transgenic models have been generated. Although over-expression of the mitochondrial Mn-superoxide dismutase (MnSOD) extends lifespan in Drosophila (Sun et al., 2002), it had no effect on lifespan in similarly over-expressing mice (Jang et al., 2009; Perez et al., 2009). An increase in ROS levels by inactivation of antioxidants does not display shortened lifespan, such that transgenic mice expressing only one allele of mitochondrial thioredoxin TRX2 do not display any decrease in life expectancy, whilst exhibiting significant defects in oxidative phosphorylation and increased hydrogen peroxide production (Jang et al., 2009). Therefore strongly suggesting that ROS generation during normal metabolism is unlikely to be the main or single cause of aging.
A causative role for mitochondrial DNA damage in the development of aging remains to be proven, however damaged mitochondrial DNA accumulates with age suggesting a potential role for mitochondrial DNA repair. Mitochondrial DNA repair defects may contribute to the accumulation of DNA damage associated with aging (Druzhyna et al., 2008; Gredilla et al., 2010a). Studies suggest that the 8-oxoG DNA lesion is one of the most abundant oxidative lesions which accumulates with age in the mitochondria. However, in apparent contrast the overall OGG1 8-oxoG glycosylase activity has been shown to increase with age in mammalian cells (Stevnsner et al., 2002b). Further studies have postulated that while the overall OGG1 content in the mitochondria increases with age, the amount of OGG1 in the mitochondrial inner compartment decreases resulting in the observed accumulation of 8-oxoG in mitochondrial DNA with a large fraction of the enzyme remaining stuck to the membrane in the precursor form, which could not be translocated to and processed in the mitochondrial matrix. (Szczesny et al., 2003). A similar observation has been reported for the mitochondrial uracil DNA glycosylase, UDG, suggesting a deficiency in import in aged cells (Szczesny et al., 2003).
Caloric restriction has been shown to reduce the accumulation of mitochondrial DNA mutations and increase lifespan (Aspnes et al., 1997; Cassano et al., 2004; Gredilla and Barja, 2005). DNA repair in the nucleus has been shown to be enhanced by caloric restriction and promote genomic stability (Heydari et al., 2007). However, studies in the mitochondria have shown that mitochondrial BER capacity did not change in liver and actually decreased in the brain and kidney of caloric restricted rats (Stuart et al., 2004). This decrease in BER correlates with the observation that mitochondria from caloric restricted rodents generate ROS and accumulate oxidative DNA damage at lower rates than non-restricted animals (Gredilla and Barja, 2005). Therefore it has been suggested that when the levels of ROS and mitochondrial DNA damage are significantly reduced, it may enable the organism to require less energy required for mitochondrial DNA repair.
Originally thought to be absent, DNA repair mechanisms in the mitochondria are now well established. Whilst all the core enzymatic components of the BER pathway have been identified in the mitochondria, the precise mechanisms of the remaining pathways have been less well investigated. For example, identification and characterization of the key players in the mitochondrial MMR pathway and a potential role for NER proteins in the repair of oxidative damage in the mitochondria remain unclear. Inactivation of many nuclear genes encoding key proteins, can impact mitochondrial DNA maintenance and result in an accumulation of DNA damage and ultimately mutations. Controversy surrounds the pathological nature of these mitochondrial DNA mutations, however increasing evidence links mitochondrial DNA integrity with carcinogenesis, neurodegenerative disease and aging. Taken together, future work requires an in dept analysis of the functional role of these mutations in human pathologies and aging.
References
1.Abu-AmeroK. K.AlzahraniA. S.ZouM.ShiY.2005High frequency of somatic mitochondrial DNA mutations in human thyroid carcinomas and complex I respiratory defect in thyroid cancer cell lines. Oncogene 2414551460
2.AkbariM.VisnesT.KrokanH. E.OtterleiM.2008Mitochondrial base excision repair of uracil and AP sites takes place by single-nucleotide insertion and long-patch DNA synthesis. DNA Repair (Amst) 7605616
3.AlamZ. I.JennerA.DanielS. E.LeesA. J.CairnsN.MarsdenC. D.JennerP.HalliwellB.1997Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J Neurochem 6911961203
4.AlexeyevM. F.VenediktovaN.PastukhV.ShokolenkoI.BonillaG.WilsonG. L.2008Selective elimination of mutant mitochondrial genomes as therapeutic strategy for the treatment of NARP and MILS syndromes. Gene Ther 15516523
5.AllegraE.GarozzoA.LombardoN.De ClementeM.CareyT. E.2006Mutations and polymorphisms in mitochondrial DNA in head and neck cancer cell lines. Acta Otorhinolaryngol Ital 26185190
6.AndersonS.BankierA. T.BarrellB. G.de BruijnM. H.CoulsonA. R.DrouinJ.EperonI. C.NierlichD. P.RoeB. A.SangerF.et al.1981Sequence and organization of the human mitochondrial genome. Nature 290457465
7.ArnheimN.CortopassiG.1992Deleterious mitochondrial DNA mutations accumulate in aging human tissues. Mutat Res 275157167
8.AspnesL. E.LeeC. M.WeindruchR.ChungS. S.RoeckerE. B.AikenJ. M.1997Caloric restriction reduces fiber loss and mitochondrial abnormalities in aged rat muscle. FASEB J 11573581
9.BacmanS. R.WilliamsS. L.MoraesC. T.2009Intra- and inter-molecular recombination of mitochondrial DNA after in vivo induction of multiple double-strand breaks. Nucleic Acids Res 3742184226
10.BalajeeA. S.DianovaI.BohrV. A.1999Oxidative damage-induced PCNA complex formation is efficient in xeroderma pigmentosum group A but reduced in Cockayne syndrome group B cells. Nucleic Acids Res 2744764482
11.BarjaG.HerreroA.2000Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals. FASEB J 14312318
12.BenderA.KrishnanK. J.MorrisC. M.TaylorG. A.ReeveA. K.PerryR. H.JarosE.HershesonJ. S.BettsJ.KlopstockT.et al.2006High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38515517
13.BerneburgM.KamenischY.KrutmannJ.RockenM.2006To repair or not to repair- no longer a question’: repair of mitochondrial DNA shielding against age and cancer. Exp Dermatol 1510051015
14.BobolaM. S.BlankA.BergerM. S.SilberJ. R.1995Contribution of O6-methylguanine-DNA methyltransferase to monofunctional alkylating-agent resistance in human brain tumor-derived cell lines. Mol Carcinog 137080
15.BobolaM. S.TsengS. H.BlankA.BergerM. S.SilberJ. R.1996Role of O6-methylguanine-DNA methyltransferase in resistance of human brain tumor cell lines to the clinically relevant methylating agents temozolomide and streptozotocin. Clin Cancer Res 2735741
16.BoeschP.IbrahimN.DietrichA.LightowlersR. N.2010Membrane association of mitochondrial DNA facilitates base excision repair in mammalian mitochondria. Nucleic Acids Res 3814781488
17.BoeschP.Weber-LotfiF.IbrahimN.TarasenkoV.CossetA.PaulusF.LightowlersR. N.DietrichA.2011DNA repair in organelles: Pathways, organization, regulation, relevance in disease and aging. Biochim Biophys Acta 1813186200
18.BohrV. A.2002Repair of oxidative DNA damage in nuclear and mitochondrial DNA, and some changes with aging in mammalian cells. Free Radic Biol Med 32804812
19.BuddM. E.CampbellJ. L.1997A yeast replicative helicase, Dna2 helicase, interacts with yeast FEN-1 nuclease in carrying out its essential function. Mol Cell Biol 1721362142
20.CaiS.XuY.CooperR. J.FerkowiczM. J.HartwellJ. R.PollokK. E.KelleyM. R.2005Mitochondrial targeting of human O6-methylguanine DNA methyltransferase protects against cell killing by chemotherapeutic alkylating agents. Cancer Res 6533193327
21.CarewJ. S.HuangP.2002Mitochondrial defects in cancer. Mol Cancer 1, 9.
22.CassanoP.LezzaA. M.LeeuwenburghC.CantatoreP.GadaletaM. N.2004Measurement of the 4834bp mitochondrial DNA deletion level in aging rat liver and brain subjected or not to caloric restriction diet. Ann N Y Acad Sci 1019, 269-273.
24.ChanK. K.ZhangQ. M.DianovG. L.2006Base excision repair fidelity in normal and cancer cells. Mutagenesis 21173178
25.ChanS. S.CopelandW. C.2009DNA polymerase gamma and mitochondrial disease: understanding the consequence of POLG mutations. Biochim Biophys Acta 1787312319
26.ChattopadhyayR.WiederholdL.SzczesnyB.BoldoghI.HazraT. K.IzumiT.MitraS.2006Identification and characterization of mitochondrial abasic (AP)-endonuclease in mammalian cells. Nucleic Acids Res 3420672076
27.ChiN. W.KolodnerR. D.1994The effect of DNA mismatches on the ATPase activity of MSH1, a protein in yeast mitochondria that recognizes DNA mismatches. J Biol Chem 2692999329997
28.ChoudhuryS.ZhangR.FrenkelK.KawamoriT.ChungF. L.RoyR.2003Evidence of alterations in base excision repair of oxidative DNA damage during spontaneous hepatocarcinogenesis in Long Evans Cinnamon rats. Cancer Res 6377047707
29.ClaytonD. A.DodaJ. N.FriedbergE. C.1974The absence of a pyrimidine dimer repair mechanism in mammalian mitochondria. Proc Natl Acad Sci U S A 7127772781
30.ClaytonD. A.SmithC. A.1975Complex mitochondrial DNA. Int Rev Exp Pathol 14167
31.CoeneE. D.HollinsheadM. S.WaeytensA. A.SchelfhoutV. R.EechauteW. P.ShawM. K.Van OostveldtP. M.VauxD. J.2005Phosphorylated BRCA1 is predominantly located in the nucleus and mitochondria. Mol Biol Cell 169971010
32.CopelandW. C.LongleyM. J.2008DNA2 resolves expanding flap in mitochondrial base excision repair. Mol Cell 32457458
33.CopelandW. C.WachsmanJ. T.JohnsonF. M.PentaJ. S.2002Mitochondrial DNA alterations in cancer. Cancer Invest 20557569
34.DaiJ. G.XiaoY. B.MinJ. X.ZhangG. Q.YaoK.ZhouR. J.2006Mitochondrial DNA 4977 BP deletion mutations in lung carcinoma. Indian J Cancer 432025
35.DarwantoA.TheruvathuJ. A.SowersJ. L.RogstadD. K.PascalT.GoddardW.3rd SowersL. C.2009Mechanisms of base selection by human single-stranded selective monofunctional uracil-DNA glycosylase. J Biol Chem 2841583515846
36.DasguptaS.HoqueM. O.UpadhyayS.SidranskyD.2008Mitochondrial cytochrome B gene mutation promotes tumor growth in bladder cancer. Cancer Res 68700706
37.DasguptaS.KochR.WestraW. H.CalifanoJ. A.HaP. K.SidranskyD.KochW. M.2010Mitochondrial DNA mutation in normal margins and tumors of recurrent head and neck squamous cell carcinoma patients. Cancer Prev Res (Phila) 312051211
38.DaviesA. M.HershmanS.StableyG. J.HoekJ. B.PetersonJ.CahillA.2003A Ca2+-induced mitochondrial permeability transition causes complete release of rat liver endonuclease G activity from its exclusive location within the mitochondrial intermembrane space. Identification of a novel endo-exonuclease activity residing within the mitochondrial matrix. Nucleic Acids Res 3113641373
39.De BontR.van LarebekeN.2004Endogenous DNA damage in humans: a review of quantitative data. Mutagenesis 19169185
40.de MouraM. B.dosSantos. L. S.Van HoutenB.2010Mitochondrial dysfunction in neurodegenerative diseases and cancer. Environ Mol Mutagen 51391405
41.de RijkM. C.RoccaW. A.AndersonD. W.MelconM. O.BretelerM. M.MaraganoreD. M.1997A population perspective on diagnostic criteria for Parkinson’s disease. Neurology 4812771281
42.de Souza-PintoN. C.MasonP. A.HashiguchiK.WeissmanL.TianJ.GuayD.LebelM.StevnsnerT. V.RasmussenL. J.BohrV. A.2009Novel DNA mismatch-repair activity involving YB-1 in human mitochondria. DNA Repair (Amst) 8704719
43.DianovG.BischoffC.SunesenM.BohrV. A.1999Repair of 8-oxoguanine in DNA is deficient in Cockayne syndrome group B cells. Nucleic Acids Res 2713651368
44.DianovG. L.Souza-PintoN.NyagaS. G.ThyboT.StevnsnerT.BohrV. A.2001Base excision repair in nuclear and mitochondrial DNA. Prog Nucleic Acid Res Mol Biol 68285297
45.DoublieS.BandaruV.BondJ. P.WallaceS. S.2004The crystal structure of human endonuclease VIII-like 1 (NEIL1) reveals a zincless finger motif required for glycosylase activity. Proc Natl Acad Sci U S A 1011028410289
46.DruzhynaN. M.WilsonG. L.Le DouxS. P.2008Mitochondrial DNA repair in aging and disease. Mech Ageing Dev 129383390
47.DuxinJ. P.DaoB.MartinssonP.RajalaN.GuittatL.CampbellJ. L.SpelbrinkJ. N.StewartS. A.2009Human Dna2 is a nuclear and mitochondrial DNA maintenance protein. Mol Cell Biol 2942744282
48.DzierzbickiP.KoprowskiP.FikusM. U.MalcE.CieslaZ.2004Repair of oxidative damage in mitochondrial DNA of Saccharomyces cerevisiae: involvement of the MSH1-dependent pathway. DNA Repair (Amst) 3403411
49.EdgarD.ShabalinaI.CamaraY.WredenbergA.CalvarusoM. A.NijtmansL.NedergaardJ.CannonB.LarssonN. G.TrifunovicA.2009Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice. Cell Metab 10131138
50.EdmondJ. C.2009Mitochondrial disorders. Int Ophthalmol Clin 492733
51.FeldmannE.SchmiemannV.GoedeckeW.ReichenbergerS.PfeifferP.2000DNA double-strand break repair in cell-free extracts from Ku80-deficient cells: implications for Ku serving as an alignment factor in non-homologous DNA end joining. Nucleic Acids Res 2825852596
52.FinstererJ.2006Central nervous system manifestations of mitochondrial disorders. Acta Neurol Scand 114217238
53.FukuiH.MoraesC. T.2009Mechanisms of formation and accumulation of mitochondrial DNA deletions in aging neurons. Hum Mol Genet 1810281036
54.GabbitaS. P.LovellM. A.MarkesberyW. R.1998Increased nuclear DNA oxidation in the brain in Alzheimer’s disease. J Neurochem 7120342040
55.GaoY.KatyalS.LeeY.ZhaoJ.RehgJ. E.RussellH. R.Mc KinnonP. J.2011DNA ligase III is critical for mtDNA integrity but not Xrcc1-mediated nuclear DNA repair. Nature 471240244
56.GotoY.NonakaI.HoraiS.1990A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348651653
57.GraziewiczM. A.BienstockR. J.CopelandW. C.2007The DNA polymerase gamma Y955C disease variant associated with PEO and parkinsonism mediates the incorporation and translesion synthesis opposite 78dihydro-8-oxo-2’-deoxyguanosine. Hum Mol Genet 16, 2729-2739.
58.GraziewiczM. A.SayerJ. M.JerinaD. M.CopelandW. C.2004Nucleotide incorporation by human DNA polymerase gamma opposite benzo[a]pyrene and benzo[c]phenanthrene diol epoxide adducts of deoxyguanosine and deoxyadenosine. Nucleic Acids Res 32397405
59.GredillaR.BarjaG.2005Minireview: the role of oxidative stress in relation to caloric restriction and longevity. Endocrinology 14637133717
60.GredillaR.BohrV. A.StevnsnerT.2010aMitochondrial DNA repair and association with aging--an update. Exp Gerontol 45478488
61.GredillaR.GarmC.HolmR.BohrV. A.StevnsnerT.2010bDifferential age-related changes in mitochondrial DNA repair activities in mouse brain regions. Neurobiol Aging 319931002
62.GruberJ.SchafferS.HalliwellB.2008The mitochondrial free radical theory of ageing--where do we stand? Front Biosci 1365546579
63.HabanoW.NakamuraS.SugaiT.1998Microsatellite instability in the mitochondrial DNA of colorectal carcinomas: evidence for mismatch repair systems in mitochondrial genome. Oncogene 1719311937
64.HaberJ. E.2000Partners and pathwaysrepairing a double-strand break. Trends Genet 16259264
65.HanesJ. W.ThalD. M.JohnsonK. A.2006Incorporation and replication of 8-oxo-deoxyguanosine by the human mitochondrial DNA polymerase. J Biol Chem 2813624136248
66.HarmanD.1956Aging: a theory based on free radical and radiation chemistry. J Gerontol 11298300
67.HarmanD.1972The biologic clock: the mitochondria? J Am Geriatr Soc 20145147
68.HarperJ. W.ElledgeS. J.2007The DNA damage response: ten years after. Mol Cell 28739745
69.HazraT. K.IzumiT.BoldoghI.ImhoffB.KowY. W.JarugaP.DizdarogluM.MitraS.2002aIdentification and characterization of a human DNA glycosylase for repair of modified bases in oxidatively damaged DNA. Proc Natl Acad Sci U S A 9935233528
70.HazraT. K.KowY. W.HatahetZ.ImhoffB.BoldoghI.MokkapatiS. K.MitraS.IzumiT.2002bIdentification and characterization of a novel human DNA glycosylase for repair of cytosine-derived lesions. J Biol Chem 2773041730420
71.HeydariA. R.UnnikrishnanA.LucenteL. V.RichardsonA.2007Caloric restriction and genomic stability. Nucleic Acids Res 3574857496
72.HockenberyD. M.2002A mitochondrial Achilles’ heel in cancer? Cancer Cell 212
73.HoeijmakersJ. H.2009DNA damage, aging, and cancer. N Engl J Med 36114751485
74.HoltI. J.HardingA. E.Morgan-HughesJ. A.1988Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331717719
75.HorvathR.KempJ. P.TuppenH. A.HudsonG.OldforsA.MarieS. K.MoslemiA. R.ServideiS.HolmeE.ShanskeS.et al.2009Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy. Brain 13231653174
76.HudsonE. K.HogueB. A.Souza-PintoN. C.CroteauD. L.AnsonR. M.BohrV. A.HansfordR. G.1998Age-associated change in mitochondrial DNA damage. Free Radic Res 29573579
77.HungW. Y.WuC. W.YinP. H.ChangC. J.LiA. F.ChiC. W.WeiY. H.LeeH. C.2010Somatic mutations in mitochondrial genome and their potential roles in the progression of human gastric cancer. Biochim Biophys Acta 1800264270
78.IchikawaJ.TsuchimotoD.OkaS.OhnoM.FuruichiM.SakumiK.NakabeppuY.2008Oxidation of mitochondrial deoxynucleotide pools by exposure to sodium nitroprusside induces cell death. DNA Repair (Amst) 7418430
79.IkedaS.OzakiK.1997Action of mitochondrial endonuclease G on DNA damaged by L-ascorbic acid, peplomycin, and cis-diamminedichloroplatinum (II). Biochem Biophys Res Commun 235291294
80.IrvineR. A.AdachiN.ShibataD. K.CassellG. D.YuK.KaranjawalaZ. E.HsiehC. L.LieberM. R.2005Generation and characterization of endonuclease G null mice. Mol Cell Biol 25294302
81.IshikawaK.HayashiJ.2010A novel function of mtDNA: its involvement in metastasis. Ann N Y Acad Sci 12014043
82.JangY. C.PerezV. I.SongW.LustgartenM. S.SalmonA. B.MeleJ.QiW.LiuY.LiangH.ChaudhuriA.et al.2009Overexpression of Mn superoxide dismutase does not increase life span in mice. J Gerontol A Biol Sci Med Sci 6411141125
83.JeongC. W.LeeJ. H.SohnS. S.RyuS. W.KimD. K.2010Mitochondrial microsatellite instability in gastric cancer and gastric epithelial dysplasia as a precancerous lesion. Cancer Epidemiol 34323327
84.JinX.ZhangJ.GaoY.DingK.WangN.ZhouD.JenJ.ChengS.2007Relationship between mitochondrial DNA mutations and clinical characteristics in human lung cancer. Mitochondrion 7347353
85.KalifaL.BeutnerG.PhadnisN.SheuS. S.SiaE. A.2009Evidence for a role of FEN1 in maintaining mitochondrial DNA integrity. DNA Repair (Amst) 812421249
86.KangD.NishidaJ.IyamaA.NakabeppuY.FuruichiM.FujiwaraT.SekiguchiM.TakeshigeK.1995Intracellular localization of 8-oxo-dGTPase in human cells, with special reference to the role of the enzyme in mitochondria. J Biol Chem 2701465914665
87.KaniakA.DzierzbickiP.RogowskaA. T.MalcE.FikusM.CieslaZ.2009Msh1p counteracts oxidative lesion-induced instability of mtDNA and stimulates mitochondrial recombination in Saccharomyces cerevisiae. DNA Repair (Amst) 8318329
88.KarahalilB.BohrV. A.De Souza-PintoN. C.2010Base excision repair activities differ in human lung cancer cells and corresponding normal controls. Anticancer Res 3049634971
89.KirkwoodT. B.2005Understanding the odd science of aging. Cell 120437447
90.KlaunigJ. E.KamendulisL. M.HocevarB. A.2010Oxidative stress and oxidative damage in carcinogenesis. Toxicol Pathol 3896109
91.KlunglandA.LindahlT.1997Second pathway for completion of human DNA base excision-repair: reconstitution with purified proteins and requirement for DNase IV (FEN1). EMBO J 1633413348
93.KraytsbergY.KudryavtsevaE.Mc KeeA. C.GeulaC.KowallN. W.KhrapkoK.2006Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet 38518520
94.KrishnanK. J.ReeveA. K.SamuelsD. C.ChinneryP. F.BlackwoodJ. K.TaylorR. W.WanrooijS.SpelbrinkJ. N.LightowlersR. N.TurnbullD. M.2008What causes mitochondrial DNA deletions in human cells? Nat Genet 40275279
95.KujothG. C.HionaA.PughT. D.SomeyaS.PanzerK.WohlgemuthS. E.HoferT.SeoA. Y.SullivanR.JoblingW. A.et al.2005Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309481484
96.KuznetsovN. A.KovalV. V.ZharkovD. O.NevinskyG. A.DouglasK. T.FedorovaO. S.2005Kinetics of substrate recognition and cleavage by human 8-oxoguanine-DNA glycosylase. Nucleic Acids Res 3339193931
97.LadnerR. D.CaradonnaS. J.1997The human dUTPase gene encodes both nuclear and mitochondrial isoforms. Differential expression of the isoforms and characterization of a cDNA encoding the mitochondrial species. J Biol Chem 2721907219080
98.LakshmipathyU.CampbellC.1999aDouble strand break rejoining by mammalian mitochondrial extracts. Nucleic Acids Res 2711981204
99.LakshmipathyU.CampbellC.1999bThe human DNA ligase III gene encodes nuclear and mitochondrial proteins. Mol Cell Biol 1938693876
100.LakshmipathyU.CampbellC.2001Antisense-mediated decrease in DNA ligase III expression results in reduced mitochondrial DNA integrity. Nucleic Acids Res 29668676
101.Le PageF.KwohE. E.AvrutskayaA.GentilA.LeadonS. A.SarasinA.CooperP. K.2000Transcription-coupled repair of 8-oxoguanine: requirement for XPG, TFIIH, and CSB and implications for Cockayne syndrome. Cell 101159171
102.Le DouxS. P.WilsonG. L.BeechamE. J.StevnsnerT.WassermannK.BohrV. A.1992Repair of mitochondrial DNA after various types of DNA damage in Chinese hamster ovary cells. Carcinogenesis 1319671973
103.LeeH. C.ChangC. M.ChiC. W.2010Somatic mutations of mitochondrial DNA in aging and cancer progression. Ageing Res Rev 9 Suppl 1, S4758
104.LeeS.ParkM. S.2002Human FEN-1 can process the 5’-flap DNA of CTG/CAG triplet repeat derived from human genetic diseases by length and sequence dependent manner. Exp Mol Med 34313317
105.LiM. X.WangD.ZhongZ. Y.XiangD. B.LiZ. P.XieJ. Y.YangZ. Z.JinF.QingY.2008Targeting truncated APE1 in mitochondria enhances cell survival after oxidative stress. Free Radic Biol Med 45592601
106.LinM. T.BealM. F.2006Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443787795
107.LindahlT.1974An N-glycosidase from Escherichia coli that releases free uracil from DNA containing deaminated cytosine residues. Proc Natl Acad Sci U S A 7136493653
108.LingF.MakishimaF.MorishimaN.ShibataT.1995A nuclear mutation defective in mitochondrial recombination in yeast. EMBO J 1440904101
109.LiuP.DempleB.2010DNA repair in mammalian mitochondria: Much more than we thought? Environ Mol Mutagen 51417426
110.LiuP.QianL.SungJ. S.de Souza-PintoN. C.ZhengL.BogenhagenD. F.BohrV. A.WilsonD. M.3rd ShenB.DempleB.2008Removal of oxidative DNA damage via FEN1-dependent long-patch base excision repair in human cell mitochondria. Mol Cell Biol 2849754987
111.LudlumD. B.1997The chloroethylnitrosoureas: sensitivity and resistance to cancer chemotherapy at the molecular level. Cancer Invest 15588598
112.LudwigD. L.MacInnes. M. A.TakiguchiY.PurtymunP. E.HenrieM.FlanneryM.MenesesJ.PedersenR. A.ChenD. J.1998A murine AP-endonuclease gene-targeted deficiency with post-implantation embryonic progression and ionizing radiation sensitivity. Mutat Res 4091729
113.MartinS. A.HewishM.SimsD.LordC. J.AshworthA.2011Parallel high-throughput RNA interference screens identify PINK1 as a potential therapeutic target for the treatment of DNA mismatch repair-deficient cancers. Cancer Res 7118361848
114.MartinS. A.LordC. J.AshworthA.2008DNA repair deficiency as a therapeutic target in cancer. Curr Opin Genet Dev 188086
115.MartinS. A.Mc CabeN.MullarkeyM.CumminsR.BurgessD. J.NakabeppuY.OkaS.KayE.LordC. J.AshworthA.2010DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1. Cancer Cell 17235248
116.MasonP. A.MathesonE. C.HallA. G.LightowlersR. N.2003Mismatch repair activity in mammalian mitochondria. Nucleic Acids Res 3110521058
117.MasudaY.BennettR. A.DempleB.1998Dynamics of the interaction of human apurinic endonuclease (Ape1) with its substrate and product. J Biol Chem 2733035230359
118.MattsonM. P.2004Pathways towards and away from Alzheimer’s disease. Nature 430631639
119.MecocciP.MacGarvey. U.BealM. F.1994Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann Neurol 36747751
120.MeierhoferD.MayrJ. A.FinkK.SchmellerN.KoflerB.SperlW.2006Mitochondrial DNA mutations in renal cell carcinomas revealed no general impact on energy metabolism. Br J Cancer 94268274
121.MichikawaY.MazzucchelliF.BresolinN.ScarlatoG.AttardiG.1999Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science 286774779
122.MiquelJ.EconomosA. C.FlemingJ.JohnsonJ. E.Jr 1980Mitochondrial role in cell aging. Exp Gerontol 15575591
123.MitaS.MonnatR. J.Jr LoebL. A.1988Resistance of HeLa cell mitochondrial DNA to mutagenesis by chemical carcinogens. Cancer Res 4845784583
124.MithaniS. K.SmithI. M.ZhouS.GrayA.KochW. M.MaitraA.CalifanoJ. A.2007Mitochondrial resequencing arrays detect tumor-specific mutations in salivary rinses of patients with head and neck cancer. Clin Cancer Res 1373357340
125.MookerjeeS. A.LyonH. D.SiaE. A.2005Analysis of the functional domains of the mismatch repair homologue Msh1p and its role in mitochondrial genome maintenance. Curr Genet 478499
126.MoothaV. K.BunkenborgJ.OlsenJ. V.HjerrildM.WisniewskiJ. R.StahlE.BolouriM. S.RayH. N.SihagS.KamalM.et al.2003Integrated analysis of protein composition, tissue diversity, and gene regulation in mouse mitochondria. Cell 115629640
127.MoroL.ArbiniA. A.YaoJ. L.di Sant’AgneseP. A.MarraE.GrecoM.2009Mitochondrial DNA depletion in prostate epithelial cells promotes anoikis resistance and invasion through activation of PI3K/Akt2. Cell Death Differ 16571583
128.MouradianM. M.2002Recent advances in the genetics and pathogenesis of Parkinson disease. Neurology 58179185
129.MullerU.TroidlC.NiemannS.2005SDHC mutations in hereditary paraganglioma /pheochromocytoma. Fam Cancer 4912
130.NagyA.WilhelmM.KovacsG.2003Mutations of mtDNA in renal cell tumours arising in end-stage renal disease. J Pathol 199237242
131.NakabeppuY.2001Molecular genetics and structural biology of human MutT homolog, MTH1. Mutat Res 4775970
132.NewlandsE. S.StevensM. F.WedgeS. R.WheelhouseR. T.BrockC.1997Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev 233561
133.NilsenH.OtterleiM.HaugT.SolumK.NagelhusT. A.SkorpenF.KrokanH. E.1997Nuclear and mitochondrial uracil-DNA glycosylases are generated by alternative splicing and transcription from different positions in the UNG gene. Nucleic Acids Res 25750755
134.ObulesuM.RaoD. M.2010DNA damage and impairment of DNA repair in Alzheimer’s disease. Int J Neurosci 120397403
135.PakendorfB.StonekingM.2005Mitochondrial DNA and human evolution. Annu Rev Genomics Hum Genet 6165183
136.ParrR. L.DakuboG. D.CrandallK. A.MakiJ.RegulyB.AguirreA.WittockR.RobinsonK.AlexanderJ. S.Birch-MachinM. A.et al.2006Somatic mitochondrial DNA mutations in prostate cancer and normal appearing adjacent glands in comparison to age-matched prostate samples without malignant histology. J Mol Diagn 8312319
137.ParrellaP.XiaoY.FlissM.Sanchez-CespedesM.MazzarelliP.RinaldiM.NicolT.GabrielsonE.CuomoC.CohenD.et al.2001Detection of mitochondrial DNA mutations in primary breast cancer and fine-needle aspirates. Cancer Res 6176237626
138.PerezV. I.Van RemmenH.BokovA.EpsteinC. J.VijgJ.RichardsonA.2009The overexpression of major antioxidant enzymes does not extend the lifespan of mice. Aging Cell 87375
139.PinzK. G.ShibutaniS.BogenhagenD. F.1995Action of mitochondrial DNA polymerase gamma at sites of base loss or oxidative damage. J Biol Chem 27092029206
140.PolyakK.LiY.ZhuH.LengauerC.WillsonJ. K.MarkowitzS. D.TrushM. A.KinzlerK. W.ogelsteinB.1998Somatic mutations of the mitochondrial genome in human colorectal tumours. Nat Genet 20291293
141.PursellZ. F.Mc DonaldJ. T.MathewsC. K.KunkelT. A.2008Trace amounts of 8-oxo-dGTP in mitochondrial dNTP pools reduce DNA polymerase gamma replication fidelity. Nucleic Acids Res 3621742181
142.RadpourR.FanA. X.KohlerC.HolzgreveW.ZhongX. Y.2009Current understanding of mitochondrial DNA in breast cancer. Breast J 15505509
143.ReeveA. K.KrishnanK. J.TaylorG.ElsonJ. L.BenderA.TaylorR. W.MorrisC. M.TurnbullD. M.2009The low abundance of clonally expanded mitochondrial DNA point mutations in aged substantia nigra neurons. Aging Cell 8496498
144.RichterC.ParkJ. W.AmesB. N.1988Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci U S A 8564656467
145.RobertsonA. B.KlunglandA.RognesT.LeirosI.2009DNA repair in mammalian cells: Base excision repair: the long and short of it. Cell Mol Life Sci 66981993
146.RogounovitchT.SaenkoV.YamashitaS.2004Mitochondrial DNA and human thyroid diseases. Endocr J 51265277
147.RoppP. A.CopelandW. C.1996Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma. Genomics 36449458
148.RothD. B.PorterT. N.WilsonJ. H.1985Mechanisms of nonhomologous recombination in mammalian cells. Mol Cell Biol 525992607
149.SageJ. M.GildemeisterO. S.KnightK. L.2010Discovery of a novel function for human Rad51: maintenance of the mitochondrial genome. J Biol Chem 2851898418990
150.SakaiY.FuruichiM.TakahashiM.MishimaM.IwaiS.ShirakawaM.NakabeppuY.2002A molecular basis for the selective recognition of 2-hydroxy-dATP and 8-oxo-dGTP by human MTH1. J Biol Chem 27785798587
151.SanderM.CadetJ.CascianoD. A.GallowayS. M.MarnettL. J.NovakR. F.PettitS. D.PrestonR. J.SkareJ. A.WilliamsG. M.et al.2005Proceedings of a workshop on DNA adducts: biological significance and applications to risk assessment Washington, DC, April 13-14, 2004. Toxicol Appl Pharmacol 208120
152.SanzA.Fernandez-AyalaD. J.StefanatosR. K.JacobsH. T.2010Mitochondrial ROS production correlates with, but does not directly regulate lifespan in Drosophila. Aging (Albany NY) 2220223
153.SchaeferA. M.Mc FarlandR.BlakelyE. L.HeL.WhittakerR. G.TaylorR. W.ChinneryP. F.TurnbullD. M.2008Prevalence of mitochondrial DNA disease in adults. Ann Neurol 633539
154.SelzerR. R.NyagaS.TuoJ.MayA.MuftuogluM.ChristiansenM.CitterioE.BroshR. M.Jr BohrV. A.2002Differential requirement for the ATPase domain of the Cockayne syndrome group B gene in the processing of UV-induced DNA damage and 8-oxoguanine lesions in human cells. Nucleic Acids Res 30782793
156.ShoffnerJ. M.LottM. T.VoljavecA. S.SoueidanS. A.CostiganD. A.WallaceD. C.1989Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy. Proc Natl Acad Sci U S A 8679527956
157.ShokolenkoI.VenediktovaN.BochkarevaA.WilsonG. L.AlexeyevM. F.2009Oxidative stress induces degradation of mitochondrial DNA. Nucleic Acids Res 3725392548
158.SimsekD.FurdaA.GaoY.ArtusJ.BrunetE.HadjantonakisA. K.Van HoutenB.ShumanS.Mc KinnonP. J.JasinM.2011Crucial role for DNA ligase III in mitochondria but not in Xrcc1-dependent repair. Nature 471245248
159.SlupphaugG.KavliB.KrokanH. E.2003The interacting pathways for prevention and repair of oxidative DNA damage. Mutat Res 531231251
161.SpiroC.PelletierR.RolfsmeierM. L.DixonM. J.LahueR. S.GuptaG.ParkM. S.ChenX.MariappanS. V.Mc MurrayC. T.1999Inhibition of FEN-1 processing by DNA secondary structure at trinucleotide repeats. Mol Cell 410791085
162.StevnsnerT.NyagaS.de Souza-PintoN. C.van der HorstG. T.GorgelsT. G.HogueB. A.ThorslundT.BohrV. A.2002aMitochondrial repair of 8-oxoguanine is deficient in Cockayne syndrome group B. Oncogene 2186758682
163.StevnsnerT.ThorslundT.de Souza-PintoN. C.BohrV. A.2002bMitochondrial repair of 8-oxoguanine and changes with aging. Exp Gerontol 3711891196
164.StierumR. H.DianovG. L.BohrV. A.1999Single-nucleotide patch base excision repair of uracil in DNA by mitochondrial protein extracts. Nucleic Acids Res 2737123719
165.StuartJ. A.KarahalilB.HogueB. A.Souza-PintoN. C.BohrV. A.2004Mitochondrial and nuclear DNA base excision repair are affected differently by caloric restriction. FASEB J 18595597
166.SunJ.FolkD.BradleyT. J.TowerJ.2002Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster. Genetics 161661672
167.SuterM.RichterC.1999Fragmented mitochondrial DNA is the predominant carrier of oxidized DNA bases. Biochemistry 38459464
168.SuzukiM.ToyookaS.MiyajimaK.IizasaT.FujisawaT.BekeleN. B.GazdarA. F.2003Alterations in the mitochondrial displacement loop in lung cancers. Clin Cancer Res 956365641
169.SwerdlowR. H.ParksJ. K.MillerS. W.TuttleJ. B.TrimmerP. A.SheehanJ. P.BennettJ. P.Jr DavisR. E.ParkerW. D.Jr 1996Origin and functional consequences of the complex I defect in Parkinson’s disease. Ann Neurol 40663671
170.SzczesnyB.HazraT. K.PapaconstantinouJ.MitraS.BoldoghI.2003Age-dependent deficiency in import of mitochondrial DNA glycosylases required for repair of oxidatively damaged bases. Proc Natl Acad Sci U S A 1001067010675
171.SzczesnyB.TannA. W.LongleyM. J.CopelandW. C.MitraS.2008Long patch base excision repair in mammalian mitochondrial genomes. J Biol Chem 2832634926356
172.TakaoM.KannoS.ShiromotoT.HasegawaR.IdeH.IkedaS.SarkerA. H.SekiS.XingJ. Z.Le X. C.et al.2002Novel nuclear and mitochondrial glycosylases revealed by disruption of the mouse Nth1 gene encoding an endonuclease III homolog for repair of thymine glycols. EMBO J 2134863493
173.TakaoM.ZhangQ. M.YoneiS.YasuiA.1999Differential subcellular localization of human MutY homolog (hMYH) and the functional activity of adenine:8-oxoguanine DNA glycosylase. Nucleic Acids Res 2736383644
174.TaschnerP. E.JansenJ. C.BaysalB. E.BoschA.RosenbergE. H.Brocker-VriendsA. H.van Der MeyA. G.van OmmenG. J.CornelisseC. J.DevileeP.2001Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene. Genes Chromosomes Cancer 31274281
175.TaylorR. W.TurnbullD. M.2005Mitochondrial DNA mutations in human disease. Nat Rev Genet 6389402
176.TellG.DamanteG.CaldwellD.KelleyM. R.2005The intracellular localization of APE1/Ref-1: more than a passive phenomenon? Antioxid Redox Signal 7367384
178.TrifunovicA.WredenbergA.FalkenbergM.SpelbrinkJ. N.RovioA. T.BruderC. E.BohloolyY. M.GidlofS.OldforsA.WibomR.et al.2004Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429417423
179.TuoJ.ChenC.ZengX.ChristiansenM.BohrV. A.2002Functional crosstalk between hOgg1 and the helicase domain of Cockayne syndrome group B protein. DNA Repair (Amst) 1913927
180.TuoJ.MuftuogluM.ChenC.JarugaP.SelzerR. R.BroshR. M.Jr RodriguezH.DizdarogluM.BohrV. A.2001The Cockayne Syndrome group B gene product is involved in general genome base excision repair of 8-hydroxyguanine in DNA. J Biol Chem 2764577245779
181.TuppenH. A.BlakelyE. L.TurnbullD. M.TaylorR. W.2010Mitochondrial DNA mutations and human disease. Biochim Biophys Acta 1797113128
182.van LoonB.HubscherU.2009An 8-oxo-guanine repair pathway coordinated by MUTYH glycosylase and DNA polymerase lambda. Proc Natl Acad Sci U S A 1061820118206
183.VartanianV.LowellB.MinkoI. G.WoodT. G.CeciJ. D.GeorgeS.BallingerS. W.CorlessC. L.Mc CulloughA. K.LloydR. S.2006The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase. Proc Natl Acad Sci U S A 10318641869
184.VermulstM.BielasJ. H.KujothG. C.LadigesW. C.RabinovitchP. S.ProllaT. A.LoebL. A.2007Mitochondrial point mutations do not limit the natural lifespan of mice. Nat Genet 39540543
185.VermulstM.WanagatJ.KujothG. C.BielasJ. H.RabinovitchP. S.ProllaT. A.LoebL. A.2008DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice. Nat Genet 40392394
186.VivekanandanP.DanielH.YehM. M.TorbensonM.2010Mitochondrial mutations in hepatocellular carcinomas and fibrolamellar carcinomas. Mod Pathol 23790798
187.WadaT.TanjiN.OzawaA.WangJ.ShimamotoK.SakayamaK.YokoyamaM.2006Mitochondrial DNA mutations and 8-hydroxy-2’-deoxyguanosine Content in Japanese patients with urinary bladder and renal cancers. Anticancer Res 2634033408
188.WallaceD. C.2001Mitochondrial defects in neurodegenerative disease. Ment Retard Dev Disabil Res Rev 7158166
189.WallaceD. C.2005A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39359407
190.WallaceD. C.ZhengX. X.LottM. T.ShoffnerJ. M.HodgeJ. A.KelleyR. I.EpsteinC. M.HopkinsL. C.1988Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease. Cell 55601610
191.WangJ.XiongS.XieC.MarkesberyW. R.LovellM. A.2005Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer’s disease. J Neurochem 93953962
192.WarburgO.1956On the origin of cancer cells. Science 123309314
193.WeissmanL.JoD. G.SorensenM. M.de Souza-PintoN. C.MarkesberyW. R.MattsonM. P.BohrV. A.2007Defective DNA base excision repair in brain from individuals with Alzheimer’s disease and amnestic mild cognitive impairment. Nucleic Acids Res 3555455555
194.XanthoudakisS.SmeyneR. J.WallaceJ. D.CurranT.1996The redox/DNA repair protein, Ref-1, is essential for early embryonic development in mice. Proc Natl Acad Sci U S A 9389198923
195.XuG.HerzigM.RotreklV.WalterC. A.2008Base excision repair, aging and health span. Mech Ageing Dev 129366382
196.YakesF. M.Van HoutenB.1997Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci U S A 94514519
197.YamaguchiH.KajitaniK.DanY.FuruichiM.OhnoM.SakumiK.KangD.NakabeppuY.2006MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Cell Death Differ 13551563
198.YangJ. L.WeissmanL.BohrV. A.MattsonM. P.2008Mitochondrial DNA damage and repair in neurodegenerative disorders. DNA Repair (Amst) 711101120
199.YoshimuraD.SakumiK.OhnoM.SakaiY.FuruichiM.IwaiS.NakabeppuY.2003An oxidized purine nucleoside triphosphatase, MTH1, suppresses cell death caused by oxidative stress. J Biol Chem 2783796537973
200.ZhangR.ZhangF.WangC.WangS.ShiaoY. H.GuoZ.2010Identification of sequence polymorphism in the D-Loop region of mitochondrial DNA as a risk factor for hepatocellular carcinoma with distinct etiology. J Exp Clin Cancer Res 29, 130.
201.ZhengL.ZhouM.GuoZ.LuH.QianL.DaiH.QiuJ.YakubovskayaE.BogenhagenD. F.DempleB.et al.2008Human DNA2 is a mitochondrial nuclease/helicase for efficient processing of DNA replication and repair intermediates. Mol Cell 32325336
202.ZsurkaG.SchroderR.KornblumC.RudolphJ.WiesnerR. J.ElgerC. E.KunzW. S.2004Tissue dependent co-segregation of the novel pathogenic G12276A mitochondrial tRNALeu(CUN) mutation with the A185G D-loop polymorphism. J Med Genet 41, e124.
Written By
Sarah A. Martin
Submitted: 25 November 2010Published: 09 September 2011