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Home  ›  How To Repair Damaged Mitochondria

How To Repair Damaged Mitochondria

Written By Tuesday, April 5, 2022 Add Comment Edit

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Mitochondrial Genome Maintenance: Damage and Repair Pathways

Submitted: October 3rd, 2022 Reviewed: Jan 22nd, 2022 Published: March 22nd, 2022

DOI: ten.5772/intechopen.84627

From the Edited Volume

Deoxyribonucleic acid Repair

Edited past Maddalena Mognato

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Abstruse

The mitochondrial genomic material (mtDNA), similarly to nuclear genome, is exposed to a plethora of exogenous and endogenous agents, also as natural processes like replication that compromise the integrity and fidelity of the mtDNA, despite the abovementioned, the mtDNA does not contain genes involved in DNA repair, therefore mitochondria completely depend on the importation of nuclear-encoded elements to achieve genome maintenance, which implies a coordinated crosstalk between these two organelles. Information technology has been determined that to counteract harm, mitochondria possess well-divers repair pathways quite similar to those of the nucleus, amid which are: base of operations excision repair (BER), mismatch repair (MMR), unmarried-strand interruption repair (SSBR), microhomology-mediated end joining (MMEJ), and probably homology recombination dependent repair (HRR). If these repair pathways are nonfunctional and the lesions remain unrepaired, the emergence of mutations, deletions, and other insults may result in compromised cellular viability and affliction.

Keywords

  • mitochondria
  • mtDNA
  • damage
  • repair
  • BER
  • MMR
  • SSBR
  • HRR
  • MMEJ

1. Introduction

The mitochondrion is an essential organelle involved principally in the production of ATP and other metabolites which are of import to several cellular functions, likewise this organelle participates in other processes as iron-sulfur cluster biogenesis, heme production, and calcium regulation [1]. The mitochondrion possesses its own circular genomic material (mtDNA), which is exposed to the same DNA lesions every bit nuclear genome is, however, unlike the latter, mtDNA does non encode for genes involved in DNA maintenance or repair which implies that these processes completely depend on nuclear-encoded elements translocated to mitochondria. It was first idea that mitochondria lacked the ability to repair its Deoxyribonucleic acid material, and this supposition was originated due to the observation of the absence of pyrimidine dimer resolution afterwards ultra violet low-cal exposition in mammalian cells [2]; all the same, present, the study of mtDNA repair pathways has evolved into a complete research area that is constantly growing, since it has been observed that mitochondria non merely possess some of the nuclear-conserved mechanisms like: base excision repair (BER), mismatch repair (MMR), single-strand break repair (SSBR), microhomology-mediated stop joining (MMEJ), and homologous recombination dependent repair (HRR), additionally mitochondria take evolved specific unique methods to deal with mtDNA insults based on the redundancy nature of mtDNA and mitochondrion itself, if the damage surpasses its repair capabilities, the mtDNA molecules tin be destroyed and replicated again or fifty-fifty the whole organelle can be degraded [3]. Of importance, lesions that remain unrepaired in mtDNA such every bit deletions, mutations, inversions, and other rearrangements have been linked to several heritable disease syndromes [iv]; farther, mtDNA rearrangements and deletions take been associated with crumbling and cancer (www.mitomap.org/org/MITOMAP) [five]. In this chapter, nosotros will summarize the different mechanisms by which the mammalian mtDNA can be damaged and the described pathways that are involved in maintenance of allegiance and integrity of mitochondrial genome.

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two. The mitochondrial genome

One of the features of mammalian cells is that they have two DNA-containing compartments: nuclei and mitochondria. Nuclear genome is large, diploid, and linear; in contrast, mitochondrial genome is polyploid and quite pocket-sized, since is formed by a 16,569 atomic number 82 circular molecule that accounts for 0.0005% of the human being genome and 0.i% of the total number of genes in the human; mtDNA is redundant, since a few hundred to few grand copies can be institute per prison cell [3], when all the copies are identical, the genotype is termed homoplasmy, instead when multiple forms exist within the aforementioned tissue or cell; the genotype is called heteroplasmy [6]. The mitochondrial genome presents 37 genes, thirteen of which encode for proteins oxidative phosphorylation chain specific and the remaining are implicated in translation: ii ribosomal RNAs (small of 12S and large of 16S) and 22 tRNAs. The grade of compaction of mtDNA is interesting since it has no introns, and the intergenic regions are almost absent-minded, additionally there are ii noncoding regions: 1 of approximately 1 kb known as noncoding region (NCR) and some other small of 30 bp, both implicated in regulation of replication and transcription [vii]. The NCR presents a triple stranded region, named D-loop, which occupies almost of its extension and is related to the start of transcription [viii], besides it has been observed that some genes overlap and others lack termination codons; therefore, it has been established that the promoters produce polycistronic transcripts which are further processed to generate mature RNA molecules [9]. As mentioned above, some of the proteins involved in respiratory system and ATP synthesis, which are extremely of import to cellular functions, are encoded past mtDNA and non the nuclear genome, thus it is important to maintain mitochondrial genome integrity to preserve homeostasis [10].

Despite the advances made in the written report of mtDNA replication mechanism, the verbal machinery and steps involved in this procedure are not fully known; all the same, it has been adamant a general caput core to this process which consists of the polymerase gamma (Polγ), a Dna helicase named Twinkle, and the mitochondrial unmarried-stranded binding protein (mtSSB) [11]. Nowadays, at that place are three proposed models to explain mtDNA replication: (1) the first is quite like to nucleus DNA replication, with standard leading and lagging strand replication, (ii) a strand deportation model, where the lagging strand is synthetized once the leading has avant-garde and synthetized a long fragment, and (3) in this model, the lagging strand is hybridized with complementary RNA, a mechanism termed RNA incorporation throughout the lagging strand (RITOL) [8]. Another interesting feature about mtDNA replication is that contrary to what occurs in nuclear genome, mitochondrial genome replication is not limited to S phase of the jail cell cycle [12].

Unlike the nucleus, where the Dna forms part of nucleoprotein complexes, consisting of Dna molecules wrapped around histone structures, the mitochondrial genome does not present histones. Information technology has been thought that this lack is responsible of the high rate of mtDNA mutagenesis, which is 10-fold greater than that in nucleus; however, this hypothesis is controversial since experimental prove has suggested that histones might provoke Dna damage instead of preventing it [3]. Despite the in a higher place, mitochondrial genome is non naked; information technology is packaged into protein-Deoxyribonucleic acid complexes, which are termed mitochondrial nucleoids due to its similarity to bacterial chromosomes [13]. The nigh arable nucleoid-associated proteins are mtSSB, transcription factor A of mitochondria (TFAM), Polγ, mitochondrial RNA polymerase (POLRMT), and Twinkle DNA helicase [14].

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3. Sources of mtDNA damage

Mitochondrial genome is exposed to almost the same insults that nuclear genome is, which can be originated past internal and external sources. Six types of Dna impairment take been proposed to be the more relevant in mitochondria [3].

3.1. Alkylation impairment

This kind of lesion may be due to exposition to exogenous agents equally chemotherapeutic drugs, diet, and tobacco fume; however, DNA alkylation damage can also exist generated from the interaction of DNA with endogenous molecules [xv], such as betaine, choline, and Southward-adenosylmethionine (SAM); the latter is the virtually relevant alkylating agent in the jail cell; SAM is a co-substrate involved in the transfer of methyl groups, when incubated with DNA in aqueous solutions leads to base of operations modification, forming small amounts of 7-methylguanine and 3-methyladenine nonenzymatically, therefore SAM acts as a weak Dna-alkylating amanuensis [16]. Of interest, these DNA modifications, in specific 7-methylguanine tin trigger the formation of mutagenic apurinic sites (AP) and imidazole ring opening which results in the stoppage of replication machinery [17]; moreover, 3-methylguanine itself is a cytotoxic Deoxyribonucleic acid lesion that also blocks replication [15]. Interestingly, mitochondria store about 30% of total hepatic SAM [18], thus mtDNA is constantly exposed to this alkylating agent, which threats its stability and integrity.

3.two. Hydrolytic damage

In that location are two types of hydrolytic impairment, the offset is the formation of AP sites equally a product of hydrolysis of the glycosidic bonds between bases and deoxyribose, and these lesions could announced due to heating, alkylation damage (previously mentioned) or by the action of N-glycosylases [19]. It has been estimated that AP is one of the most frequent lesions in the Dna, with approximately 10,000 lesions per cell, per day [20]. Interestingly, typical AP sites generate base of operations pair modifications, since there is a preference to incorporate adenine opposite to AP by polymerases during DNA replication [21]. The other form of hydrolytic harm is the hydrolytic deamination of bases, where cytosine and its homolog v-methylcitosine are mainly affected. It is noteworthy that the conversion of cytosine to uracil may introduce punctual mutations to the genome during replication if left unrepaired [20].

3.3. Formation of adducts

This type of lesions can exist generated for exposition to ultraviolet blazon B and C calorie-free which produce bulky DNA adducts termed photodimers, in addition, activated metabolites of several organic contaminants, for instance, polycyclic aromatic hydrocarbons and mycotoxins may bring almost adducts [1]. On the other hand, adduct formation can also be stimulated by endogenous factors, for example, it has been demonstrated that reactive intermediate products of diethylstilbestrol metabolization form Deoxyribonucleic acid adducts preferentially with mitochondrial genome, where these insults are suggested to avoid replication and/or transcription, thus producing mtDNA instability in vivo [22].

3.4. Mismatches

During replication, polymerases can introduce base of operations to base mismatches too every bit generate nucleotide insertions or deletions in mitochondria, which are normally known as insertion-deletion loops (IDLs). One of import source of mismatches are damaged deoxyribonucleotide triphosphates (dNTPs), predominantly oxidized, which can be incorporated to DNA during synthesis [three, x].

3.v. DNA strand breaks

These injuries are divided based on the breaking of one or both strands. Single strand breaks (SSBs) can be generated by normal cellular procedures that went wrong, such every bit erroneous or abortive action of Dna topoisomerase I (Top1), which presents mitochondrial localization, and when information technology fails may produce poly peptide-linked DNA breaks [23], too SSBs are produced by ineffective base of operations excision repair (BER), or by oxidative stress [24]. One lesion related to SSBs is the germination of a covalently linked AMP to a five′ phosphate, production of an unsuccessful DNA ligase activity [25]. On the other paw, double strand breaks (DSBs) are the most harmful, since they can provoke global cellular responses that involve many aspects of jail cell metabolism [26]. These lesions may occur by endogenous agents like reactive oxygen species (ROS), errors in Dna metabolism past topoisomerases, and nucleases or detention of replisome. On the other paw, lesion can be caused by exogenous insults such as ionizing radiation and chemotherapeutic drugs [1].

3.6. Oxidative damage

In living organisms, ROS are normally produced as a consequence of endogenous metabolic reactions and also past external factors. ROS include superoxide anion (Oii −), hydrogen peroxide (H2O2), hydroxyl radical (OH−), and single oxygen (O2), all of them can oxidize Dna molecules and generate several types of impairment including oxidized bases and unmarried- and double-strand breaks [15]. Oxidative damage is by far the most prevalent and studied in mtDNA, since mitochondria are an important contributor in the creation of ROS [27], generated past the leakage of electrons from the electron transportation concatenation (ETC) [28], and there are at least nine sites responsible for generating the superoxide anion [29]. The importance of ROS affecting mtDNA lies in the observation that oxidative harm accumulates in several human diseases [30]. Of interest, it has also been reported that reactive nitrogen species (RNS) are able to oxidize or deaminate Dna and produce strand breaks, lesions that could be possible in mtDNA since these RNS can be plant in mitochondria [31, 32].

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4. Mitochondrial DNA repair mechanism

Well-nigh of the repair pathways used past mitochondria to deal with its damaged DNA are quite similar to those operating in the nucleus; this ascertainment makes sense when we realize that mitochondrion relies completely in import of DNA repair elements encoded by nuclear genome, despite that mitochondrial genome does not contain any gene implicated in repair; it appears that the mitochondrial version of the repair machinery operates with fewer proteins than the nuclear counterparts [33] (Figure ane).

Figure 1.

Mitochondrial import and mtDNA repair pathways. The elements that participate in mitochondrial genome maintenance are nuclear encoded; therefore, mitochondria need to import these effector proteins, which are involved in different repair pathways.

4.1. Base excision repair (BER)

Base of operations excision repair (BER) is the deputed pathway to removed nonbulky lesions similar alkylated, deaminated, and oxidized bases from the DNA. This pathway has been well studied in the nucleus and was the showtime repair mechanism reported in mitochondria and to date the best characterized in this last organelle [33, 34]. BER mechanism is highly conserved from leaner to humans and basically comprises v stages: (1) recognition and excision of the damaged base of operations, (2) removal of the abasic site formed, (3) Dna end processing, (4) repair synthesis, and (v) ligation [35], and at the same time, BER can exist divided into two branches (both founded in mitochondria): short patch and long patch, where the deviation lies in the process used to repair, while brusk patch forms a single nucleotide gap, long patch forms a bigger one of 2–10 nucleotides [36]. Ane of the chief elements involved in BER processes are the Dna glycosylases, enzymes that catalyze the excision of the North-glycosidic bond between the altered base of operations and its corresponding sugar, thus creating an abasic site, and activeness that was showtime observed by Lindahl et al. [37]. These glycosylases can be subdivided into monofunctional or bifunctional, depending on whether they have lyase activity or not, ability that determines the type of harm they can repair, while monofunctional glycosylases focus on nonoxidative impairment, bifunctional exert their action confronting oxidized Dna bases [35]. In mammalian mitochondria, vii glycosylases take been reported, iii monofunctional: uracil-Deoxyribonucleic acid glycosylase (UNG1), E. coli MutY homolog (MYH), and North-methylpurine Dna glycosylase (AAG/MPG) and 4 bifunctional: 8-oxoguanina-Dna glycosylase (OGG1), E. coli endonuclease III homolog (NTH1) endonuclease VIII-like glycosylase 1 and 2 (NEIL1 and 2) [38, 39, 40, 41]. Afterward the activeness of glycosylases, the adjacent stride, DNA finish processing, is catalyzed by nuclear BER enzymes that are also constitute in mitochondria, equally apurinic-apyrimidinic endonuclease 1 (APE1) and polynucleotide kinase-3′-phosphatase (PNKP) [35], further the synthesis is carried out by the main mitochondrial polymerase (Polγ). It was recently reported that polymerase beta (Polβ) also localizes within mitochondria, whereas similar to the nucleus, it has a relevant role in mtDNA maintenance and mitochondrial homeostasis through its participation in BER [42]. It has as well been observed that FEN1, DNA2, and EXOG are involved in the removal of DNA flap generated by polymerase strand displacement synthesis [43]. Finally, the ligation activity is made by mitochondrial ligase III [44]. In conclusion, despite that BER is the almost characterized pathway in mitochondria, information technology is still unknown whether all the nuclear elements are conserved in mitochondrial BER, or on the reverse, if this pathway accept specific proteins that practice non participate in nuclear version of BER, it is not well understood either which are the regulatory signals that controls the import of these elements to mitochondria.

iv.ii. Nucleotide excision repair (NER)

Nucleotide excision repair (NER) pathway is a complex mechanism involved in recognition of lesions, adducts or structures that modifies the Dna double helix structure, having the possibility of blocking transcription, replication, and thus affecting Dna stability. I of the most important features of NER is its versatility on a wide kind of lesions since they are detected and repaired. Roughly, the process starts with damage recognition, next, the damaged strand is cleaved at both sides of the lesion to be removed after, so the missing sequence is synthesized using the complementary strand as a template, and finally the ends are ligated, thus restoring DNA sequence and integrity [45].

At that place is a large trunk of evidence reporting the absence of nucleotide excision repair activity in mitochondria. The first observation about this lack was made past Clayton et al. in 1974 [2], who reported that mitochondria were unable to remove UV-induced pyrimidine dimers. Equally a result, lesions that are normally repaired in nucleus by NER could persist in mitochondrial genome; this damage is not merely restricted to photodimers, since NER likewise participates in repair of other bulky lesions and a subset of oxidative DNA harm [ane]. In the nucleus, bulky lesions tin can also be overcome through the use of specialized translesion synthesis (TLS) polymerases; however, in mitochondria, the major polymerase (Polγ) presents a weakly thymine dimer bypass action in vitro and at present, information technology is unknown whether this activity is conserved in vivo [46]. On the other mitt, it was recently reported that polymerase theta (Polθ), an enzyme that acts every bit a translesion featherbed polymerase, thus promoting the pass of replicative stalling lesions in the nucleus [47], is localized to mitochondria. Additionally, it was observed that there is an increase of Polθ localization to mitochondria after treating the cells with an oxidative agent, suggesting that the enzyme is recruited to the organelle when this kind of damage is inflicted, where it could facilitate translesion bypass synthesis. Interestingly, in POLQ KO cells, the charge per unit of point mutation in mtDNA was significantly reduced after oxidative handling; this observation indicates that Polθ is involved in a pathway of error-prone DNA synthesis that may facilitate replication in mitochondria [48].

Despite that the nucleotide excision repair pathway has not been clearly recognized in mitochondria, there are several proteins involved in the nuclear version of this pathway that not simply localize to the organelle just also they accumulate upon oxidative damage, and when they are depleted from cells, the number of point mutation is increased, observations that strongly advise their participation in mtDNA maintenance. Some of these proteins are: Cockayne syndrome A (CSA), Cockayne syndrome B (CSB), and Rad23A [48, 49, 50]. Therefore, further investigation is needed to completely rule out NER pathway from mitochondria, or to elucidate whether these mentioned proteins are involved in other pathways different to nucleus.

four.iii. Mismatch repair (MMR)

MMR is a highly conserved pathway involved in the correction of misincorporation and slippage mistakes committed by polymerases during Deoxyribonucleic acid replication, and base mismatches generated past base of operations deamination, alkylation, and oxidation [3]. In general terms, MMR procedure presents the next steps: localization of the mismatch and identification of the newly synthesized strand, excision at both extremes of the mismatch lesion, DNA resynthesis, and finally ligation to complete the process [ten].

The first demonstration of mammalian mitochondria capable to repair mismatch lesions was washed by Mason et al. [51]. They observed that rat liver mitochondrial lysates repaired G-T and G-Thousand mismatches; notwithstanding, by using immunodetection no MSH2, a primal nuclear element in MMR, was detected in these lysates, suggesting that mitochondrial MMR activeness uses different elements to those of the nucleus. Posteriorly, in the pursuit of proteins responsible for the activeness observed, one study reported that mismatches and small IDLs in mitochondrial genome are recognized past the Y-box binding protein i (YB1), which as well localizes to nucleus where information technology exerts other functions, and its depletion in cultured cells triggers an increased mutagenesis in mtDNA. In add-on, it was demonstrated that MMR activity is contained of MSH2 and that MSH3, MSH6 or MLH1 are non present in human mitochondria, at least under the experimental weather condition employed [52]. In dissimilarity to the previous ascertainment, it was later demonstrated that MLH1 do localizes to mitochondria [53]. Through overexpression of Mlh1 or Msh2 in retinal endothelial cells, it was determined that MLH1 has a protective role in mtDNA afterward glucose-induced DNA harm, and on the other hand, this protective outcome was not detected when Msh2 was overexpressed, observation that suggests no participation in mtDNA maintenance [54], in accordance with previous studies. Additionally, it was reported that the incidence of base of operations-mismatches in mtDNA in diabetic retina is a consequence of expression silencing of MLH1 by methylation of its promoter, activity performed by Dnmt1, enzyme overexpressed in diabetes. Thus, these observations propose that MLH1 has an important part in mtDNA maintenance, since its silencing by methylation triggers mtDNA impairment [55]. In summary, MMR pathway is involved in mitochondrial genome maintenance; all the same, not all the elements implicated take been institute. It could exist possible that the proteins of mitochondrial MMR may have a different splicing or mail translational versions than nuclear ones, which impairs their identification through antibody-based techniques, or in the other hand, mitochondrial MMR could not depend of all the elements involved in the canonical nuclear form, equally it was seen with the participation of YB1 [52]. In whatever example, more than enquiry is needed to discover more MMR nuclear factors within mitochondria or to discover new ones and be able to itemize the mitochondrial MMR equally an original pathway.

4.iv. Single strand break repair (SSBR)

The repair of SSBs in mitochondria is achieved through a BER subpathway known as base excision/SSB repair (which is also present in nucleus), since both mechanisms share common component, especially in the last steps: gap filling and DNA ligation [10, 24]. Indeed, almost of the SSBs tin be repaired past elements of BER pathway: APE1, PKPK, and Polγ [24]. Other members of mitochondrial SSB repair include: PARP1, a protein implicated in the detection of SSBs in the nucleus and likewise more recently observed in mitochondria, where not but information technology binds to mtDNA, but likewise when is depleted, this provokes accumulations of DNA damage, thus confirming its participation in mtDNA maintenance [56]. Besides, the participation of ExoG in SSB repair has been elucidated, since its depletion induces mitochondrial persisting SSBs that somewhen lead to apoptosis [57].

Equally was previously mentioned, there are some lesions associated to SSB, like trapped topoisomerase one (Top1), damage that can be repaired through the activeness of tyrosil-DNA phosphodiesterase i (TDP1), an of import enzyme involved in the release of covalently trapped Top1 with Dna that was first described in yeast [58]. In add-on to its well characterized function, it has been observed that TDP1 as well removes other types of 3′-blocking lesions, resulting oxidative damage [59, lx, 61]. A fraction of TDP1 (nuclear encoded) localizes to the mitochondria, where it has been implicated in mtDNA repair, since the handling with chain terminator nucleotide analogs (CTNAs), which are also substrates of this enzyme, in tdp1 −/− cells generate a reduction in mtDNA copy number, whereas wild type cells remain unaffected [61, 62]. These findings confirm the interest of TDP1 in mtDNA harm repair, in this instance induced by CTNAs. Another SSB-related lesion is the generation of a covalent binding of adenine monophosphate (AMP) to the 5′end of mtDNA, and this error is promoted by abortive ligase activity. The resolution of such damage relies in aprataxin (APTX) poly peptide that is able to remove 5′-adenylate groups. APTX localizes to mitochondria, whereas its depletion generates a decline of mtDNA re-create number as well as college levels of DNA damage, observations that suggest a directly role of this enzyme in mtDNA maintenance [63]. If whatever of the lesions mentioned remains unrepaired, farther complications may appear, since SSBs may progress to DSBs, which are more deleterious to cells.

four.5. Double strand break repair (DSBR)

In general, cells of college eukaryotes apply two main approaches to repair DSBs. The first arroyo is through the union of the ends in a nonhomologous dependent fashion, this pathway is termed nonhomologous end joining (NHEJ); it has been determined that NHEJ possesses some alternatives versions that use noncanonical elements, these sub pathways are known as culling NHEJ (A-NHEJ); the repair with these mechanisms guarantee the restoration of DNA integrity merely not sequence.

4.5.one. Nonhomologous stop joining (NHEJ)

Nonhomologous end joining (NHEJ) is one of the two master pathways used by the cells to repair Dna double strand breaks. Similar to most DNA repair processes, NHEJ is based on three general steps: the action of a nuclease to resect the damaged DNA, next, the fill-in to make new Deoxyribonucleic acid by a polymerase, and finally the participation of a ligase to restore the integrity of the strands. One of the most interesting features of NHEJ is the diversity of substrates that can apply and convert to joined products [64]. By virtue of its template-independent operation, NHEJ is associated with insertions and deletions and hence with a lack of reliable restoration [26].

It has been observed that mammalian mitochondria do possess the capacity to demark Dna ends, activity that is retained even in Ku-deficient cells [65], additionally, the efficiency and precision of this activeness apparently depend on the construction of the ends generated, since blunt-ended DNA fragment repaired are less conserved than gluey ends in comparison to the original [66]. Tadi et al. [67] demonstrated that mitochondria have a noncanonical version of NHEJ, also named alternative NHEJ (A-NHEJ). The repair by this pathway is based on microhomology and is sometimes associated with long deletions, and hence it is described equally microhomology-mediated end joining (MMEJ). In this same study, using rodents and human mitochondrial extracts, a lack of end-to-end joining of nonligatable broken Dna was observed, the fact that suggests the absenteeism of a functionally operative canonical NHEJ in mitochondria, or at least is undetected with the techniques used. In contrast, mitochondria have the ability to join oligomeric dsDNAs harboring direct repeats (microhomology) that vary in length, from 5 to 22 nt, with an efficiency that is enhanced with the increase in the length of homology. These results are supported by a previous observation, where DSBs are induced in mice through mitochondrially targeted brake endonuclease ( Pst I), and the repaired mtDNA presented pocket-sized directed repeats (a few nucleotides) at the breakpoint [68], resolution that fits with the repair manner of MMEJ, and in addition, these repair products have also been observed in near of the mtDNA deletions associated with human being diseases, which are generally (~85%) flanked by small direct repeats [69]. Besides, it has been determined that this mitochondrial MMEJ activity involved the proteins CtIP, FEN1, Mre11, PARP1, and ligase 3 [67].

Therefore, MMEJ has been proposed equally a central pathway in the repair of double strand breaks and maintenance of mammalian mitochondrial genome, and the use of this pathway and possibly not C-NHEJ may explicate the Ku independence proteins to exert the joining activeness as was previously mentioned. The possible absenteeism of C-NHEJ activeness in mitochondria is contrasting with the observation that antibodies to KU70 and KU80 cross-react with proteins from mitochondrial extracts with Deoxyribonucleic acid terminate-binding activity [10, 70]. Furthermore, it has been determined that XRCC4, a mediator protein of nuclear DSB repair pathway, is present in mitochondrial, where information technology is indeed involved in mtDNA repair and possibly associated with Dna ligase 3 [48]. In summary, at nowadays no NHEJ activeness has been described in mitochondria; nonetheless, this organelle presents the ability to join cleaved Deoxyribonucleic acid ends, and it appears that this activity depends on the structure of the ends generated and in the presence of homology at both ends of the DSB, further, the repair past MMEJ may explain the deletions observed in the bulk of mitochondrial diseases.

iv.5.2. Homologous recombination (Hr)

Homologous recombination (HR) is a ubiquitous procedure conserved from bacteriophages to humans and is one of the most important pathways used by the cells to deal with DNA double strand breaks. To achieve the restoration of molecular integrity and sequence in a free-error manner, Hour needs a homologous sequence to use it as a template [26, 71].

It has been determined that Hr is essential for preservation of mtDNA in plants, yeast, and fungi, and on the other hand, although at that place is testify nearly HR in mammalian, its significance in vivo is non clear [i]. One of the first reports about mitochondrial homologous repair capabilities was made by Thyagarajan et al. [72] where they observed that mitochondrial protein extracts from mammalian cells catalyzed homologous recombination repair of plasmid DNA substrates, therefore concluding that mitochondria exercise possess the mechanism to perform this process. Additionally, afterwards preincubating protein extracts with anti-RecA antibodies, an inhibition of the reaction was observed, fact that suggests the participation of a mammalian mitochondrial RecA homolog. Supporting this evidence, in 2022, Sage et al. [73] demonstrated that Rad51 and the related proteins, Rad51C and XRCC3, localize to man mitochondria, and they as well reported that the protein levels were enriched later on stress consecration and that depletion of any of these elements generates a dramatic decrease in mtDNA copy number, these results strongly advise some type of 60 minutes participation in mitochondrial genome maintenance. Other proteins involved in 60 minutes have been observed in mitochondria, and their participation in mtDNA repair has been validated, such every bit Dna2 [74] and Mre11 [67, 75, 76]; moreover, it has been suggested that ExoG could supply Exo1, and therefore, many of the factors needed to perform Hr procedure are present in mitochondria.

Recently, using biochemical assays, information technology was adamant that HR is the major DSBR mechanism, where it has a role in maintenance of mitochondrial genome integrity, since the induction of DSBs significantly enhanced this process. Likewise the participation of Rad51, Mre11 and Nibrin relevance in Hr was confirmed past suppression of HR-mediated repair after immunodepletion of these proteins in the mitochondrial extracts [76]. The process of mitochondrial HR may proceed in 2 means, ane through intramolecular recombinant events, where a sole mtDNA molecule recombines with itself, and a second form, where a molecule can recombine with some other i homologous or heterologous [77, 78]. Despite the noesis of the elements involved in mitochondrial 60 minutes have increased over the last years, the verbal machinery about how 60 minutes is achieved in mitochondria is lacking in comparison to the nuclear models [33].

The second approach is through the utilise of nondamaged homologous sequences; this kind of repair restores molecular integrity also as sequence; another pathway that uses homology sequences is single strand annealing (SSA), which needs directed repeats in both ends of the DSB, in such a way that when repairing, information technology restores integrity and sequence only at the expense of a variable length deletion [26].

4.6. Other pathways

As it has been previously described in this chapter, mitochondria take a repertoire of elements to deal with DNA harm, even it has been observed that mitochondria possess a mechanism to "prevent" further lesions (described below). However, if the mtDNA lesions surpass the mitochondrial repair capabilities, the cell maintains other options to avoid a higher damage, and in these circumstances, it is possible to degrade the unrepairable mtDNA, the organelle or fifty-fifty the whole cell [10].

4.6.1. Sanitation of the dNTP pool

The DNA is not the just molecule susceptible to chemical damage, the deoxyribonucleotide triphosphates (dNTPs) puddle is also affected, being oxidative damage one of the most recurrent alterations [79]. If unrepaired, these lesions could become a source of mismatch errors during Deoxyribonucleic acid synthesis [3]. To cope with this threat, mitochondria take MTH1, an specialized enzyme also institute in the nucleus, which tin can hydrolyze oxidized dNTPs such as 8-oxo-xx-deoxyguanosine triphosphate (eight-oxo-dGTP), 8-oxo-20-deoxyadenosine triphosphate (8-oxo-dATP), and 2-hydroxy-20-deoxtadenosine triphosphate (2-hydroxy-ATP) to corresponding monophosphates, which cannot exist assembled in the Dna past polymerases [41, 80]. In 2008, Pursell et al. [81] reported that 8-oxo-dGTP exists in some rat tissues at levels that are potentially mutagenic; therefore, these information advise that oxidized dNTP precursors could generate mutagenesis in vivo and consequently promote mitochondrial dysfunction. In addition, it was reported that a pathogenic variant of Polγ, which is present in patients with progressive external ophthalmoplegia (PEO), increases 8-oxo-dGTP misincorporation, ascertainment that establishes a relationship between the oxidative lesions and increased mtDNA damage observed in other models with this pathogenic version, and misincorporation of oxidized nucleotides [82]. In summary, although sanitation of premutagenic free nucleotides is not properly a Dna repair mechanism, its participation prevents the germination of mismatches in mitochondrial genome and therefore reduces the probability of mutagenesis.

4.six.2. mtDNA degradation

Compared to nuclear genome, mitochondrial genomic material has a remarkable advantage most DNA impairment and repair, its back-up, consisting of hundreds to thousands of copies per prison cell. Due to this feature, mitochondria tin can dispose of a considerable fraction of mtDNA, where its repair capabilities were exceeded; notwithstanding, it does not compromise organelle functions, and this is not an pick for nucleus, where the diploid genome cannot be submitted to degradation without affecting the cellular homeostasis [3]. It is thought that later mtDNA degradation, the lost molecules are restored by mitochondrial genome turnover, a process that was offset described several decades ago [83] (Figure two). There is a wide torso of testify that supports this hypothesis of mtDNA degradation afterwards unrepairable insults; for example, it was observed that when one of the initial steps of the BER repair pathway is inhibited by methoxyamine drug, the increase of incidence of oxidative and alkylating damage enhanced the mtDNA degradation [84]; additionally, through qPCR analysis, it has been shown a mtDNA amount subtract subsequently persisting exposure with the oxidizing agent hydrogen peroxide [85, 86]. Furthermore, the absence of mutation fixation later persisting cell treatment with alkylating agents which have a high mutagenic potential suggests that due to the lack of mechanisms for repairing bulky lesion, the mtDNA could be selectively degraded and to prevent farther modifications [87]. Nowadays, it is not completely clear how the mitochondrion degrades its damaged DNA; however, it has been recently determined that endonuclease G (EndoG) has an important role in mtDNA depletion, since it promotes cleavage of mtDNA as a response to oxidative and nitrosative stress, activeness that subsequently generates an upregulation of mtDNA replication every bit an indirect outcome [88]. This evidence is supported by the fact that endo 1000 is the most arable and active nuclease within mitochondria, and it has a preference on oxidized DNA harboring single-strand breaks or distorted Dna production of crosslinking agents to exert its endonuclease activity in vitro [89], too it has been reported that this nuclease preferentially cleaves 5-hydroxymethylcytosine an oxidized production of 5-methylcytosine [xc]. In decision, despite that additional enquiry is needed to elucidate the whole mechanisms and elements that participate in mtDNA degradation, this pathway emerges as a unique and mitochondrial specific method to maintain DNA integrity.

Effigy ii.

mtDNA degradation and mitophagy. (A) Damaged mtDNA (yellow circles) tin can be selectively degraded inside mitochondria, thus keeping "healthy" mtDNA (greenish circles), so this can replicate to re-plant mitochondrial genome homeostasis. (B) If the mtDNA is severely damaged and the repair mechanism is surpassed, injured mitochondria can exist selectively degraded by the germination of an autophagosome and subsequent fusion with lysosomes [91]. On the other manus, the mtDNA lesions tin also trigger cell apoptosis.

4.6.3. Mitochondrial clearance, dynamics, and apoptosis

In general terms, autophagy is a highly conserved degradative mechanism used by cells to maintain homeostasis [92]. This is a finely regulated procedure that takes function in cell growth, evolution, and in the maintenance of an equilibrium between synthesis, degradation and recycling of cellular elements including whole organelles [11]. At that place is a specialized sub pathway of autophagy, which is specifically involved in deposition of damaged and dysfunctional mitochondria, and this procedure is known as mitophagy or mitochondrial clearance. Although mitophagy can emerge as a programmed cellular event, like the 1 that is observed during erythroblast maturation in lodge to generate mature red blood cells lacking mitochondria [xi], it has been proposed that mitophagy could participate in the elimination of organelles harboring low levels of Dna harm stress. On the other hand, when the DNA lesions are too many to handle with mtDNA repair machinery or past mitochondrial clearance, the cellular response could trigger apoptosis [93], therefore the choice of which pathway must be used depends on the degree of DNA harm (Figure two). In accord with the previous mechanism, Suen et al. [94] observed selectively deposition by mitophagy of organelles harboring deleterious COXI mutations after overexpressing the protein Parkin, which translocated to affected mitochondria and induced autophagic emptying, thus this pick enriched cells for nonmutated mtDNA and restoring cytochrome c oxidase activity [95].

It appears that mitophagy is closely associated with mitochondrial dynamics processes: fission and fusion [96]. Fusion is the joining of two organelles to form one, this mechanism allows mitochondria to distribute mtDNA and to replenish it when is damaged, therefore safeguarding mtDNA integrity and protecting it from mutations [97]. On the other hand, fission is the division of a single organelle to create 2, this procedure is very important to cellular viability, it contributes to symmetrical distribution of mitochondria during mitosis, and promotes the removal of lesioned organelles by partitioning the damaged elements (similar mtDNA) to a derived mitochondria that tin can fuse to a healthy one with the intention of recovering functionality or to be degraded by mitophagy. Therefore, mitochondrial removal past mitophagy is preceded by mitochondrial fission, which is capable of dividing the organelle into smaller pieces to be degraded easily [98]. When mitochondrial clearance, fusion, or fission are dysfunctional, the cells could be severely afflicted, since it has been observed that in these situations, an increase in mtDNA instability and generation of neurodegenerative, cardiovascular, and age-related diseases were obtained [99].

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5. mtDNA repair, diseases, and aging

Mitochondrial diseases are a heterogeneous group of illnesses affecting multiple organs and leading to eventual degeneration and in some cases premature decease. These affectations have origin in mutations on mtDNA, which are generated past errors during Deoxyribonucleic acid replication, exogenous sources, and ROS; however, mitochondrial dysfunction may also arise from mutations in nuclear genes which encode proteins with mitochondrial function, involved in several processes like biogenesis, transcription, replication, mitochondrial dynamics, and mtDNA repair, among others. Of involvement, neurodegeneration is a prevalent trait in mitochondrial diseases, maybe because the brain needs a higher demand of free energy in comparison with other tissues [11]. On the other hand, there is a large body of evidence that underscores the relationship between mitochondrial disorders and aging; however, there is still controversy virtually whether these mutations in the mtDNA are the production of historic period-related disorders or they are themselves the cause [100].

Virtually the genes involved in mtDNA maintenance, it has been well established that failure of the mtDNA repair pathways may promote diseases and historic period-related disorders in humans [11, 28]; in add-on to mutations, the reduction of mtDNA re-create number has also been associated with neurodegeneration, crumbling, diabetes, and cancer [101]. For example, information technology has been observed that the lack of proofreading activity of Polγ in mice generates multi-systemic disease and phenotypes resembling to premature aging [102], furthermore, over 200 mutations in POLG accept been associated with mitochondrial diseases, these POLG-related disorders tin be classified into five primary phenotypes of neurodegeneration: Alpers-Huttenlocher syndrome (AHS), childhood myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and PEO [28], besides, mutations in Twinkle helicase ofttimes causes infantile onset spinocerebellar clutter (IOSCA), which normally appears in early on childhood [103]. Other mtDNA repair elements, such as APTX and TDP1, implicated in SSBR, are related with the generation of ataxia with ocular motor apraxia (AOA1) when are mutated [10, 104]. Likewise, defects in the proteins CSA and CSB, implicated in the possibly mitochondrial DNA repair transcription coupled-NER pathway, are related with the evolution of progressive cerebellar pathology [105]. Furthermore, alterations in fusion, fission, or mitophagy processes due to mutations in the proteins involved generate mtDNA instability, which in turn may induce neurodegenerative, cardiovascular, and age-related diseases [99], such is the case of MFN2, which is implicated in mitochondria fusion, and its alteration lead to organelle fragmentation and causes axonal Charcot-Marie-Tooth illness (CMT2A) [106], also mutations in OPA1, lead to optic cloudburst, arrayal that can exist accompanied with hearing loss and ophthalmoplegia [107]. Additionally, mutations in DNA2 and mitochondrial genome maintenance exonuclease 1 (MGME1) nucleases are implicated in ophthalmoplegia, myopathy, and mtDNA depletion [108, 109]. In conclusion, the importance of mtDNA maintenance lies in the observation that when the repair elements are afflicted, or the mechanisms exceeded, the run a risk of disease development increases, thus the understanding of these alterations may shed low-cal for clinical targets to foreclose diseases or treat them.

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6. Final remarks

After decades of study, it has been ended that like nucleus, mitochondria do possess specific mechanisms to maintain integrity of its small and polyploid genome, and although nowadays, the complete repertoire of elements participating in mtDNA repair has not been identified, it appears that these pathways resemble those of nucleus just operating with fewer elements. In addition, mitochondria take evolved organelle specific mechanisms which work as a backup when the repair pathways are surpassed past the corporeality of damage and that would be impossible to comport out in nuclear genome. In determination, the repair of mitochondrial genome is a field in continuous growth that promises new discoveries in the years to come.

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Written Past

Ulises Omar García-Lepe and Rosa Ma Bermúdez-Cruz

Submitted: Oct 3rd, 2022 Reviewed: January 22nd, 2022 Published: March 22nd, 2022

© 2022 The Author(s). Licensee IntechOpen. This affiliate is distributed nether the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted utilise, distribution, and reproduction in any medium, provided the original work is properly cited.

Source: https://www.intechopen.com/chapters/65844

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