The most frequent deletion in human mtDNA encompasses ca. 5 kbp. This deletion includes most of the complexes of the ETC, leading to an overall bioenergetic deficit
[43]. While it is not entirely understood how mtDNA deletions occur, several hypotheses were suggested: In most cases, mtDNA deletions occur randomly and appear to undergo clonal expansion. Another theory suggests that critical pathways for mtDNA replication and quality control are impaired in neurodegenerative disorders
[40]. The maintenance of mtDNA requires a variety of nDNA-encoded gene products. The proteins involved in mtDNA replication have been termed replisome
[50]. The mtDNA replisome consists of the mtDNA polymerase γ (a complex of
POLG and
POLG2 gene products), the mitochondrial transcription factor (
TFAM), the DNA helicase twinkle (
TWNK), and the mitochondrial single-stranded binding protein (
mtSSB)
[50]. Remarkably, variants in
POLG,
TWNK, and
TFAM are not only known as a monogenic cause of primary mitochondrial disorders (occasionally presenting with parkinsonism) but can also increase the risk for PD
[51]. Based on the known function of the mitochondrial replisome, mutations in these three genes can result in mtDNA deletions and decreased mtDNA copy numbers
[49]. All three genes show high expression levels in neuroanatomical key structures involved in PD disease development such as the substantia nigra (SN)
[51]. Postmortem studies also revealed lower levels of mtDNA transcription factor
TFAM in the SN of PD patients
[52]. In this study,
TFAM and
TFB2M levels correlated with decreased expression levels of complex I. Noteworthy, decreased mtDNA copy numbers showed a cell-specific distribution in PD
[53]. In contrast to dopaminergic neurons of the SN, cholinergic neurons isolated from PD brains were associated with a higher mtDNA copy number
[54]. It is also worth mentioning that many of the known monogenic PD genes (e.g.,
PRKN or
LRRK2) have been linked to altered mtDNA maintenance
[55][56][57]. However, future studies are needed to fully understand the interconnectedness of mtDNA maintenance and their impact on monogenic and idiopathic PD.
Even though mtDNA alterations have been observed in physiological aging, the increased amount of mtDNA rearrangements and deletions in PD patients suggest a certain disease specificity
[58]. Accordingly, SN-related mtDNA deletions and copy number variations are more common in PD than in patients with other neurodegenerative diseases (e.g., Alzheimer’s disease, AD)
[41]. PD patients are thus more likely to accumulate mtDNA mutations, particularly in dopaminergic neurons. Therefore, regulation of mtDNA deletions and copy number variations seems to be a potential mechanism to protect SN neurons from cell death or apoptosis.
Additional experimental evidence originates from animal models. A conditional
TFAM knock-out mouse (MitoPark mouse) is characterized by respiratory chain deficiencies and low neuronal cell counts including progressive loss of dopaminergic neurons in the SN
[59][60][61]. In another mouse model, mutant
TWNK has been expressed in CNS neurons, leading to an increase of age-related mtDNA deletions and dopaminergic neurodegeneration
[62]. These mice suffer from levodopa-responsive motor impairment and show phenotypic features of premature aging. This data stresses that the integrity of the nuclear and the mitochondrial genome is critical for the survival of dopaminergic neurons.
The deepened understanding of mtDNA defects in PD may offer the opportunity for targeted therapies: mtDNA deletions in individual SN neurons can activate compensatory mechanisms mainly by triggering mitochondrial biogenesis
[63][64]. These mechanisms increase the number of mtDNA copies, the formation of cristae networks, and dopamine synthesis. The compensatory response could be impaired or dysregulated by nDNA variants in the genes mentioned above and may impact PD onset and progression
[35]. By employing compensatory mechanisms, individual neurons can overcome the harmful effects of mtDNA mutations below a certain threshold
[64]. The increase of mtDNA copy numbers with a corresponding rise in wild-type mtDNA might therefore prevent respiratory chain defects in people with a high mtDNA deletion burden. Therefore, the enhancement of mitochondrial biogenesis could be specifically targeted by gene therapy to combat the unspecific accumulation of mtDNA mutations in PD patients
[65].