Biomedical Engineering Reference
In-Depth Information
may be stimulated by Ca
++
, which induces the activity of
mitochondrial metabolic processes and inhibits proper action of
the respiratory chain (
22
) (and Chap. 2). Moreover, mitochon-
drial overproduction of ROS may arise directly by perturbation of
the respiratory chain, such as inherited or acquired respiratory
deficiencies (
61
), as well as by a number of other sites, including
the enzymes 2-oxo glutarate dehydrogenase and aconitase (
60
).
Further, ROS may be produced by the electron transfer flavopro-
tein (ETF)/ETF quinone oxidoreductase (ETFQO) complex
(
62
), and by still undefined sites in organic acidemias caused by
mitochondrial enzyme deficiencies, including fatty acid oxidation
deficiencies (
63, 64
). In mitochondrial enzyme deficiencies,
including fatty acid oxidation deficiencies, glutaryl-CoA dehydro-
genase deficiency, propionic and methylmalonic acidemias, it has
been indicated that the observed oxidative stress was initiated by
induction of NO, giving rise to lipid oxidation and membrane
distortion. However, large numbers of patients with mitochon-
drial enzyme deficiencies harbor missense gene variations, coding
for misfolding enzyme proteins, which - together with loss of
enzyme function and toxic accumulation of metabolites - may
contribute to the patophysiology, including oxidative stress
(
48, 65, 66
).
Despite the fact that oxidative stress as a patophysiological
consequence of intra- as well as extra-mitochondrial stressors in
most cases is considered to be created by increased production of
o
2
•
from the respiratory chain, a decrease in the antioxidant
defense may also contribute in certain cases. Indeed, in the men-
tioned mitochondrial enzyme deficiencies the total radical-
trapping antioxidant potential (TRAP) has been found decreased
(
63, 64
). Further, and probably more relevant in the present con-
text, SOD2/MnSOD, the mitochondrial superoxide dismutase,
is down-regulated in the neuronal model of Alzheimer's Disease
mentioned above (
25
). Additionally, we have observed reduced
expression of SOD2 in cultured fibroblasts from patients with
SCAD deficiency (
88
) and decreased resistance to menadione
created O
2
−
in fibroblasts from patients with this and other mito-
chondrial fatty acid oxidation defects (Zolkipli et al. 2009,
unpublished).
Thus, down-regulation of the intra-mitochondrial enzymatic
defense may be under-appreciated simply because it has not been
investigated.
The regulatory mechanisms of the respiratory chain, includ-
ing production of ROS, and of the antioxidant system, including
enzymatic and non-enzymatic antioxidants, are extremely com-
plex and a detailed discussion of them is outside the scope of the
present text. What is interesting here is that small alterations in
the ROS production and elimination rates are capable of shifting
the balance from physiological healthy to pathological. As previously
Search WWH ::
Custom Search