What Role Does Mitochondrial Stress Play in Neurodegenerative Diseases? - Protein Misfolding and Cellular Stress in Disease and Aging - page 70

mitochondrial membranes ( 75 ). This association may even be
extended to PD-related proteins besides a-synuclein. As men-
tioned above, PINK1 has been shown to both influence mito-
chondrial morphology and function. Parkin, associated with
familial forms of PD, is recruited selectively to dysfunctional
mitochondria with low membrane potential for mitophagy elimi-
nation. Failure to remove these dysfunctional organelles contrib-
utes to the pathogenesis of PD in these families ( 76, 77 ).
A mitochondrial involvement with huntingtin aggregates has
been described for Huntington's disease (HD). The mutant hun-
tingtin protein, which aggregates once the CAG polyglutamine
repeat reaches a certain critical threshold, has been shown to
directly affect energy metabolism (ATP/ADP ratio), Dy m , and
intracellular Ca +2 levels ( 78 ). Mutant huntingtin has also been
showed to cause a transcriptional repression of PGC-1a, a tran-
scription factor regulating the control of mitochondrial biogene-
sis in the cell, leading to another source of dysfunction indirect
from immediate associations with the mitochondria ( 79 ).
Likewise, impairment in mitochondrial function has also been
reported in mouse models of ALS that involve mutations in the
Cu, Zn superoxide dismutase (SOD1). Both wild-type and
mutant G93A-SOD1 have been found to reside inside the mito-
chondrial matrix with mutant SOD1 forming high molecular
aggregations here in an age and symptomatic-dependent manner
( 80 ). Overexpression of the copper chaperone responsible for the
maturation of SOD1 in the G93A-SOD1 transgenic mouse back-
ground leads to an accelerated neurodegenerative phenotype,
mitochondrial vacuole formation, and increasing OXPHOS
deficiencies ( 81 ).
Mitochondrial perturbations in astrocytes and other glia-
derived cell types can potentiate death in neurons. ALS-associated
G93A-SOD1 mutation in astrocytes displays severe impairment
of oxygen consumption and ADP respiratory control causing a
decline in motor neuron survival ( 82 ). Microglia activates neu-
roinflammatory responses where it synergistically acts with
a-synuclein overexpression models to contribute to the demise of
dopaminergic neuron ( 83 ).

5.2. Future Directions
on Aggregates
and Mitochondrial
Dysfunctions

Although there has been direct evidence that abnormal or over-
abundant accumulations of aggregation-prone proteins affect
mitochondria, the causal mechanism is still a topic of debate.
Complex IV dysfunction in AD was suggested to precede and
perhaps initiate AD-protein aggregation; however, recently this
was disproven as complex IV impairment has been shown to
decrease Ab accumulations in a mouse model ( 84 ). A more likely
scenario is one in which the abnormal Ab accumulation affects
mitochondrial function and synaptic function (reviewed in ( 85 )).