Biomedical Engineering Reference
In-Depth Information
4. Reactive Oxygen
Species Role in
Neurodegene-
ration
Due to the high-energy demand of brain tissues, impairments in
OXPHOS can have particularly severe consequences in the CNS.
ATP synthesis is highly correlated with brain activity levels (
50
).
However, mitochondrial oxidative functions may cause unwanted
damage to the system over time. The electron transport chain
(ETC) is not perfect and mitochondria produce reactive oxygen
species (ROS) from an estimated 0.2-2% of the oxygen con-
sumed. Most of this production is observed at complexes I and
III where large changes in the energy potential of electrons rela-
tive to oxygen levels occur (reviewed in (
51
)). ROS are free stable
oxygen-based molecules with an unpaired electron with the abil-
ity to be donated or accepted by DNA, proteins, fatty acids, or
other biological molecules causing unwarranted modifications.
Superoxide molecules (O
2
−
) can also react with hydrogen to
become hydrogen peroxide (H
2
O
2
). Although ROS can have
functional roles, such as promote cell growth (
52
), they can also
signal apoptosis and global changes in gene expression (reviewed
in (
53
)). The mitochondria has evolved multiple defense mecha-
nisms against ROS to neutralize hydrogen and oxygen-based
insults (reviewed in (
54
)). Superoxide dismutase 1, 2 (SOD1,
SOD2), glutathione and catalase are antioxidant defense enzymes
used to scavenge these molecules to safely deduce them to hydro-
gen peroxide or H
2
O and O
2
, respectively. ROS is a recognized
source of damage the cell needs to protect itself against. Although
it is generally accepted that oxidative damage is part of the aging
process (reviewed in (
55
)), the exact role of ROS in normal aging
and neurodegeneration is far from understood.
4.1. Aging, ROS, and
Neurodegeneration
The free radical theory of aging states that a vicious cycle of free
radical damage harming mtDNA and OXPHOS machinery leads
to the feedforward production of more ROS (
56
). However, a
number of recent reports provided evidence against this hypoth-
esis. In the polg model, which was discussed earlier, even though
the causation of why these mice have defective OXPHOS func-
tioning is unknown, they do not show increased ROS levels in
the brain (
41, 42
). And, other genetic defects decreasing
OXPHOS function do not seem to lead to increases in ROS or
oxidative stress (reviewed in (
57
)). Also, common mouse
mtDNA variants display different phenotypes with changes in
ROS levels and ROS sensitive enzymes all seemingly compen-
sate to have the same overall cellular respiration between differ-
ent haplotypes (
58
).
There is conflicting evidence that ROS plays a role in age-
related degeneration. It seems that superoxide formation has a
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