4 III is a splice variant from the LIG3 gene encoding for both the nuclear and mitochondrial enzymes. The mechanism of action as well as the interaction with other proteins of the mitochondrial variant of DNA ligase III is still unclear. 3.3. Mitochondrial BER Proteins, Organization, and Inter- actions. Some of the proteins involved in mtDNA repair have been described to be components of the nucleoids [62, 63]. One of the essential components of the nucleoids is the mitochondrial transcription factor A (TFAM) that plays a signiﬁcant role in the organization and structure of the mitochondrial nucleoids [64, 65]. TFAM has recently been associated with mtBER activity, modulating DNA repair eﬃciency in mitochondria [66]. Likewise, essential proteins of the mtBER like polγ, in particular its accessory subunit polGβ, have also been described to be key factors in the organization of these nucleoprotein complexes [67]. Investigations on how the organization of mtDNA in mito- chondria aﬀects and modulates BER is increasing, and recent studies have suggested that mtDNA association to the inner membrane is critical for proper base excision repair [68]. Moreover, the cockayne syndrome group B (CSB) protein, which was thought to be present exclusively in the nucleus, has been recently localized to mitochondria [33]. Mutations in the CSB gene are responsible for the Cockayne syndrome, a segmental premature aging syndrome [69]. The Cockayne syndrome is associated with severe development deﬁciencies and neurodegeneration. The CSB protein plays a role in genomic maintenance and transcription regulation in the nucleus, and it had also been suggested to play a role in mtBER, although the mechanism was obscure [4]. Recent studies have indicated that CSB may play a role in general mitochondrial maintenance [70]. Interestingly, the investiga- tion on CSB protein and its location in mitochondria have suggested that CSB protein could play a direct role in mtBER by interacting and stabilizing BER proteins in the protein- DNA complexes associated with the inner mitochondrial membrane when mtDNA repair takes place [33]. 4. Mitochondrial DNA Damage, DNA Repair, and Aging The increased susceptibility to cellular loss and the pro- gressive functional decline observed during aging has been associated with accumulation of damage to macro- molecules, particularly to mtDNA [10, 13]. According to the mitochondrial-free radical theory of aging free radicals generated by mitochondria are the main contributors to the accumulation of damage. Over the years, several inves- tigations have linked mitochondrial ROS production and accumulation of mtDNA mutations to the aging process, and because mtDNA repair mechanisms are essential in order to avoid increased accumulation of mtDNA mutations, they are thought to play an important role in the aging process [2]. Although mitochondrial ROS and mtDNA mutations were supported as main contributors of aging mainly by descrip- tive data and correlative studies, the generation of a knock-in mouse expressing proof-reading deﬁcient polγ, but conserv- ing its replicative function, is considered by some authors Journal of Aging Research as an important support of accelerated mtDNA mutation rate resulting in increased aging rate [12, 71]. This mouse model, the mutator mouse, appears as an interesting model in which to investigate the causative link between mtDNA mutation accumulation and aging, and the role that mtBER may play in the process [72, 73]. In various tissues of this mouse model, mtDNA point mutations as well as mtDNA deletions have been described to accumulate at a much higher rate than in the wild-type mice [12, 71, 74]. However, how the accumulation of mtDNA mutations lead to the loss of mitochondrial function and aging is still discussed [74]. Investigations on brain and heart samples have suggested that it is the accumulation of large mtDNA deletions and clonal expansion, instead of mtDNA point mutations, that drive the premature aging phenotype [16, 75]. However, after performing research on hepatic and cardiac tissues, Edgar et al., recently reported that circular mtDNA molecules with large deletions represent only a minor proportion of the total mtDNA in this mouse model and suggested that random point mutations occurring in mtDNA are the driving force behind the premature aging phenotype [76]. Discrepancies could be due, at least in part, to the diﬀerent mechanisms that have been suggested to be responsible of the generation of mtDNA mutations in postmitotic and mitotic tissues [77]. It has been proposed that in postmitotic cells, such as neurons, mtDNA deletions occur primary during repair of damaged DNA, whereas in mitotic tissues mtDNA point mutations are more likely to be caused during replication [78]. This could lead to signiﬁcant diﬀerences in the type of mtDNA mutations being detected in postmitotic and mitotic cells during normal aging. Thus, for substantia nigra neurons from aged individuals and Parkinson’s disease patients, direct evidence exists of mitochondrial dysfunction due to accumulation of mtDNA deletions [79, 80], while mtDNA point mutations have been reported to occur rarely in these neurons during aging [77]. If mtDNA deletions are actually generated during repair of damage mtDNA, alteration in mtBER ﬁdelity with age would play an important role in mtDNA deletion accumulation and aging. A recent study has reported the presence of large linear mtDNA fragments in liver mitochondria in the mutator mouse model [81]. The authors suggest that due to the increased errors inserted during DNA synthesis, replication arrest would occur as a result of an eﬀort to execute DNA repair. In a scenario of a high mutant load, replication pausing would be extended and strand breakage would likely occur at pause sites, leading to formation of mtDNA linear fragments. Although the level of these mtDNA fragments does not increase with age in the mutator mice, Bailey et al. [81] suggest that the long- term impact of aberrant mitochondrial DNA replication might contribute to the premature aging phenotype of these mutator mice. Moreover, they suggest that as a result of aberrant mitochondrial replication, essential factors involved in DNA metabolism would be mobilized to mitochondria and eventually would become exhausted. Because nuclear and mitochondrial DNA metabolism share several of those essential factors, the collapse of DNA factors in mitochondria could probably have an impact on nuclear DNA metabolism, contributing to the premature aging phenotype.