What Role Does Mitochondrial Stress Play in Neurodegenerative Diseases? - Protein Misfolding and Cellular Stress in Disease and Aging - page 62

stimulation ( 2 ). Not only are mitochondria involved in the
presynaptic side of the cell, but also at the postsynapse. The post-
synaptic dendritic morphology, plasticity, and quantity rely on
mitochondrial mobilization to postsynaptic densities regulated in
an activity dependent manner ( 3 ). This type of plasticity alters
different postsynaptic targets mediating different mitochondrial
demands on the presynaptic side of the cell causing differences in
Ca +2 buffering mechanisms and dynamics ( 4 ).
Specialized proteins have been discovered for the specific
movement of mitochondria for axonal transport. The Drosophila
protein, Milton, discovered through genetic mutational screens,
was the first neuronal-specific mitochondrial transport protein
identified for synapse and terminal mitochondrial localization ( 5 ).
Miro and kinesin heavy chain (KHC) build a complex with Milton
to facilitate anterograde movement down microtubules depen-
dent on the absence or presence of Ca +2 in the synapse ( 6 ). Miro
seems to act as the calcium sensor in this complex to determine
where mitochondria should be released and positioned around
postsynaptic sides of the synapse where glutaminergic neuronal
activity induces large Ca +2 fluxes ( 7 ).
Besides trafficking, mitochondria have an intrinsic need to
fuse and segregate from each other to maintain normal operations.
Fis1 and Drp1 are responsible for fission; while mitofusins (Mfn1,
Mfn2) and OPA 1 mediate fusion events (reviewed in ( 8 )).
Although the mechanisms responsible for what benefits fusion and
fission provide for mitochondria are unknown, alterations in their
balance lead to cell death. Disturbances in either fusion or fission
as opposed to improper trafficking have been found to be consis-
tently associated with neurodegenerative diseases.

2.1. Familial Mutations
of Genes Associated
with Mitochondrial
Dynamics

Mutations found in genes ubiquitously expressed in the body that
control mitochondrial fusion and fission events have been found
to cause exclusive neurodegenerative events (reviewed in ( 9, 10 )).
By examining pedigrees of familial cases of dominant optic atro-
phy (DOA) and Charcot Marie Tooth 2A (CMT2A) patients,
frameshift and missense mutations were found in GTPase mito-
chondrial fusion proteins OPA1 and Mitofusin2, respectively ( 11,
12 ). DOA selectively causes the loss of retinal ganglion cells, and
CMT2A affects axonal periphery sensorimotor neuropathy.
Studies examining the molecular basis behind these mutations
reveal the importance behind mitochondrial morphology, dynam-
ics, and its relation to these degenerative observations. In the case
of OPA1, the dysfunction of this protein leads to a fragmented
mitochondrial network, causes a loss of mitochondrial membrane
potential (Dy m ), and upregulates the release of cytochrome c into
the cytoplasm increasing apoptosis ( 13 ). More work is needed to
dissect the molecular mechanisms behind defects of Mfn2 seen in
CMT2A. However, defects in Mfn2 created by a region specific-