What Role Does Mitochondrial Stress Play in Neurodegenerative Diseases? - Protein Misfolding and Cellular Stress in Disease and Aging - page 68

strong inverse relation to maximum lifespan potential (LSP); and
the rate of neurodegeneration is also inversely related to LSP
( 59 ). Whether this is actually a causal relationship is unknown.
Nuclear DNA undergoes ROS damage in a regional specific man-
ner in the brain increasing with age ( 60 ). These different regional
damages seen in protein carbonyl modifications by ROS also seem
to have correlated age-associated decline behaviorally in cogni-
tion and motor coordination ( 61 ). But definitive evidence dem-
onstrating that differences in brain regions or neuronal populations
have different amounts of ROS production or energy consump-
tion demands has yet to be shown.

Seemingly, although nonmitochondrial ROS production from
lipid metabolism, cytosolic enzymes, and NADPH oxidases are
thought to contribute only a tenth of what mitochondrial
sources of ROS do, they are often associated with neurodegen-
erative diseases. This has been most extensively shown with AD,
but not exclusively. AD brains with abnormal ceramide metabo-
lism and free cholesterol levels had increased 4-hydroxynoneal
(HNE) adducts that are indicative of oxidative modifications,
but from a nonmitochondrial source of damage ( 62 ). HNE
adducts are found to be highly reactive and when decreasing
aldehyde dehydrogenase 2 activity in transgenic mice, there are
increases in ROS adjunct proteins and neurodegeneration with
decreases in cognition ( 63 ). In addition, mitochondrial ROS
may be a secondary contributor after an initial activation of
NADPH oxidase by Ab in AD causing the dysfunction of sup-
porting astrocytes unable to maintain neurons ( 64 ). Recently,
the involvement of NADPH oxidase as the main contributor to
superoxide formation, as opposed to having a mitochondrial
origin, was associated with excitotoxic NMDA receptor-medi-
ated death in primary culture and in vivo ( 65 ). These studies
reinforce the idea that mitochondria are not the sole generators
of ROS.

4.2. Nonmitochondrial
Sources of ROS and
Neurodegeneration

How much ROS damage produced by mitochondrial dysfunc-
tion leads to neuronal cell death in diseased states? It is not
clear whether the source of this damage is in any way mito-
chondrial based during each neurodegenerative insult. The
effects of oxidative stress are frequently reported; however, the
measurements of the quantity and source are not easy to per-
form or interpret. Conclusions cannot be drawn from isolated
mitochondria preparations held with reduction/oxidization
conditions at unnatural states. The relationship between mito-
chondrial function, ROS damage, and neurodegeneration is
not clear-cut, as these three can possibly be very separate and
independent phenomena.

4.3. Future Directions
on the Mitochondrial
ROS and
Neurodegeneration
Connection