What Role Does Mitochondrial Stress Play in Neurodegenerative Diseases? - Protein Misfolding and Cellular Stress in Disease and Aging - page 63

targeted knockout in the cerebellum caused a shortening of the
Purkinje cells' dendritic length eventually leading to death, which
seems to be caused by defects in oxidative phosphorylation
(OXPHOS) activity as a result of an abnormal segregating mito-
chondrial DNA (mtDNA) pool leaving some cells without a
genome in some mitochondria ( 14 ). This need for mitochondrial
fusion does not seem restricted to developmental requirements,
but rather to an intrinsic need to maintain mitochondrial function
in different tissues (reviewed in ( 15 )).

2.2. Mitochondrial
Dynamics Involvement
in Common
Neurodegenerative
Diseases

Mitochondrial dynamics recently have been found to be affected
in the four most common neurodegenerative diseases: Parkinson's
disease (PD), Huntington's disease (HD), Amyotrophic lateral
sclerosis (ALS) and Alzheimer's disease (AD). Each of these neu-
rodegenerative diseases shows an age-related loss of dopaminer-
gic substantia nigra pars compacta neurons, striatal spiny neurons,
and cortical/hippocampal neurons, respectively. PTEN-induced
kinase 1 (PINK1) is a gene, mutated in forms of recessive familial
cases of PD, where deficiency leads to PD with decreases in cate-
cholamine release, quanta release, and diminishing long-term
potentiation synaptic plasticity ( 16 ). PINK1 has been found to
regulate mitochondrial fission through Drp1 and Fis1, and muta-
tions in these genes cause defects in mitochondrial morphology
( 17 ). However, this may not be a sole regulatory role for dynam-
ics. Knocking out PINK1 has also been shown to affect other
mitochondrial functions causing decreases in cell respiration,
membrane potential, and calcium-handling capacities ( 18 ).
Amyloid beta (Ab), known to accumulate as different oligomers
in AD, also plays a role in affecting mitochondrial dynamics as
well and seems to be responsible for a fragmented morphology
leading to an abnormal cellular distribution ( 19 ). An even more
direct connection showed that Ab at physiological levels caused
increases in S-nitrosylation of Drp1, thus increasing GTPase activ-
ity leading to mitochondrial fission events, increased cell death,
and decreased the quantity of dendrites ( 20 ). The N¢ terminus of
mutant huntingtin protein in HD also has been shown to associ-
ate with mitochondria and inhibit its trafficking ability in striatal
cultures ( 21 ). The CAG repeat length on huntingtin increases the
propensity for mitochondria to fragment, which is abrogated by
overexpression of Mfn2 or a dominant negative Drp1K38A ( 22 ).
Most recently, familial mutations in the ALS associated -Cu, Zn,
superoxide dismutase (SOD1) protein have been shown to induce
mitochondria fragmentation and impair trafficking ( 23 ). Defects
in mitochondrial dynamics are beginning to appear as phenotypes
in more common neurodegenerative diseases as opposed to iso-
lated neurodegenerative cases where mutations are found directly
affecting mitochondrial fission/fusion proteins. Although these
changes are likely secondary, they may play an important role in
the pathophysiology of these diseases.