Biomedical Engineering Reference
In-Depth Information
stress (
87
). Additionally, in another astrocytic cell line, stably
expressing the same variant SCAD protein, we observe induction
of the mitochondrial superoxide dismutase (MnSOD or SOD2),
most pronounced after exposure to mild heat-stress (40°C) for
24 h (
87
).
These experiments indicate that regardless the origin of mis-
folded proteins, the perturbation of mitochondria function and
creation of oxidative stress most probably provide the first steps
of the patophysiological manifestations of protein misfolding dis-
eases. Despite the sparse knowledge about the exact mechanisms
by which misfolded proteins create oxidative stress, it is today
common wisdom that oxidative stress is implicated in a large
number of diseases of which the neurodegenerative diseases as
well as disorders of the respiratory chain are the best known (
16
).
Thus, notwithstanding the eliciting factors, oxidative stress is
important, especially because - once created - it propagates the
vicious cycle of oxidatively modified/damaged proteins, which
enhance misfolding and increase the oxidative stress, etc.
Since the main source of ROS production is the mitochon-
dria, it is appropriate to discuss the creation, regulation, and gen-
eral molecular effects of mitochondria-mediated oxidative stress.
5. Oxidative Stress:
Creation,
Regulation, and
Molecular Effects
Creation of mitochondrial oxidative stress is due to an imbalance
between production and elimination of ROS and RNS. ROS
comprises the primary produced superoxide (O
2
-
˙
) as well as sec-
ondary products, such as hydrogen peroxide (H
2
O
2
) and hydroxyl
radical (HO
·
) (
29
), all of which can modify/damage DNA, lipids,
and proteins. The main source of RNS in the form of NO is nitro-
gen oxide synthetases (NOSs) (
22, 23
), which may react with
simultaneously produced O
2
-
˙
to form the highly reactive per-
oxynitrite, ONOO
-
. Both H
2
O
2
and NO function as redox regu-
lators of various transcription factors. Their production is therefore
necessary for normal physiological function (
56-59
), requiring
continuous survey of the amounts, especially by the ROS defense
systems, comprising a multitude of antioxidant enzymes, includ-
ing superoxide dismutases (SOD1 and 2), glutathione (GSH),
glutathione reductases, and peroxidases as well as catalase, thiore-
doxins, and thioredoxin reductase (
29, 60
). However, these sys-
tems may be overwhelmed or down-regulated with consequential
damaging oxidative stress.
As mentioned earlier, mtNOS, is stimulated by Ca
++
, and
overproduction of NO may thus be a consequence of calcium
influx and activation of mtNOS (
22, 23
). Likewise, ROS production
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