What Role Does Mitochondrial Stress Play in Neurodegenerative Diseases? - Protein Misfolding and Cellular Stress in Disease and Aging - page 64

2.3. Future Directions
on Mitochondrial
Dynamics

The importance of mitochondrial dynamics seems to be much
more crucial to neuronal cell types than other cells as mutations
of fission/fusion proteins found in these patients are ubiquitous
in nature, but their disease states are only characterized by a
selective neuronal loss of a certain population. The most com-
mon suggestion to answer why this is may be that the long dis-
tance mitochondria have to travel in axons would make neurons
more susceptible to defects in mitochondrial dynamics. Definite
proof of this model is lacking. However, new studies have now
begun to show associations between Mfn2 and Miro/Milton
complexes tying together mitochondrial dynamics and traffick-
ing in neurons ( 24 ). Another interesting question is whether the
differences in which neurons become susceptible is related to
specific energy demands different neuronal types may have. The
mechanisms associated with neuronal death and defects in mito-
chondrial dynamics also remain to be elucidated. With increasing
evidence that mitochondrial dynamics contributes to neurode-
generative disease, it will be important to understand whether
these changes are causal or secondary characteristics of neuronal
cell death.

3. Mitochondrial
DNA Mutations
and Their
Occurrences
in Neurons

Besides the nuclei, mitochondria are the only animal organelles
that contain multiple copies of their own genome, which code for
37 genes: 13 polypeptides, 22 transfer RNAs, and 2 (small and
large) ribosomal RNAs. Mitochondrial DNA (mtDNA) in humans
is 16,569 base pairs-long and it contributes to oxidative phospho-
rylation (OXPHOS) components needed for ATP production. In
an assembly line fashion, the electron chain transports electrons
through Complexes I-IV to drive a protein gradient in the inner
membrane space for Complex V, an ATPase synthase pump to
produce adenosine triphosphate (ATP). Mitochondrial DNA,
which is transcribed and translated in the mitochondria, contrib-
utes subunits to all of these complexes except Complex II ( 25 ).
A connection between senescence, mtDNA deletions, and
neuronal dysfunction has been reported; however, the details to
date are still unclear. Aging postmortem brain tissues of healthy
individuals and those suffering from neurodegenerative diseases
show accumulation of partially deleted mtDNAs ( 26, 27, 28 ). The
most commonly reported deletion in humans, named the “common
deletion,” of 4,977 base pairs in length lies between nucleotides
8,470-8,483 to 13,447-13,459 and is thought to arise by intramo-
lecular recombination, possibly because of the stalling of the mtDNA
polymerase during replication of the genome (reviewed in ( 29 )).
Replication of the genome is not the only way to introduce large-
scale deletions found in mtDNA. Pauses in replication can also cause