What Role Does Mitochondrial Stress Play in Neurodegenerative Diseases? - Protein Misfolding and Cellular Stress in Disease and Aging - page 65

double-strand breaks (DSB) that are recombinogenic. Accordingly,
DSB in mtDNA, elicited by restriction enzymes targeted to mito-
chondria in vivo , undergo homologous and nonhomologous
repair to create a multiple array of diverse deletions. Using a mouse
model with a mitochondria-targeted restriction endonuclease, it
was shown that partially deleted mtDNAs had a replicative advan-
tage over the full-length wild-type molecule in both postmitotic
neurons and muscle fibers ( 30, 31 ). Natural mechanisms of dou-
ble-strand breaking could occur during replication pausing, ultra-
violent radiation, or oxidative stress with repair of these damages
as a source for deletions (reviewed in ( 32 )). In postmortem tis-
sues, these partially deleted mtDNAs were found at different levels
in regionally different areas within the human brain ( 27 ). Because
their overall levels are relatively low, the functional significance of
these mutated mtDNA species is unknown. However, the accu-
mulation of mtDNA deletions at relatively high levels (40-60%)
has been reported in the aging substantia nigra, and these high
deletion levels were associated with a cytochrome c oxidase (COX)
deficiency in individual neurons ( 26, 33, 34 ).
These large missing portions of DNA spanning the mitochon-
drial genome are not the only alterations found over time in aging
organisms. Somatic point mutations in the mtDNA can lead to both
silent, missense, and nonsense mutations varying in the degrees of
functional change depending on their location. In human AD
patients, there is an increase in the amount of point mutations accu-
mulating in the control region of the genome positively correlating
with age ( 35 ). However, this finding may not extend to the rest of
the genome as an increased burden of mutations was also found in
age-matched patients whether they were AD positive or nondis-
eased ( 36 ). In a Drosophilia melanogaster model where mtDNA
point mutations were introduced in the germline, animals harbor-
ing different base pair substitutions changing the amino acid code
in the cytochrome c oxidase subunit I gene showed age-related neu-
rodegenerative phenyotypes and myopathies ( 37 ).

Transgenic mouse models affecting the repair or replicative abili-
ties of the mtDNA in neuronal specific populations have been
reported. A targeted dopaminergic mitochondrial transcription
factor A (TFAM) knockout mouse developed parkinsonian-like
symptoms after severe mtDNA depletion causing a specific loss of
this neuronal population ( 38 ). Another TFAM knockout mouse tar-
getting forebrain neurons showed similar results in this different
population of neurons leading to COX-deficient cells, neuronal loss,
astrogliosis, and increased suspectibility to kaniac acid insults ( 39 ).
Trans-neuronal degeneration has also been reported in chimeric
mitochondrial late-onset neurodegeneration (MILON) mice. Defect
in specific neurons caused the death of both neurons with mtDNA
depletion (caused by TFAM deletion) and normal OXPHOS

3.1. Models of mtDNA
Deletions/Mutations
Mimicking
Neurodegeneration