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2. Mitochondrial inhibition and oxidative stress: reciprocating players in neurodegeneration
Zeevalk GD, Bernard LP, Song C, Gluck M, Ehrhart J.
Antioxid Redox Signal. 2005 Sep-Oct;7(9-10):1117-39.
Although the etiology for many neurodegenerative diseases is unknown,
the common findings of mitochondrial defects and oxidative damage posit
these events as contributing factors. The temporal conundrum of whether
mitochondrial defects lead to enhanced reactive oxygen species
generation, or conversely, if oxidative stress is the underlying cause
of the mitochondrial defects remains enigmatic. This review focuses on
evidence to show that either event can lead to the evolution of the
other with subsequent neuronal cell loss. Glutathione is a major
antioxidant system used by cells and mitochondria for protection and is
altered in a number of neurodegenerative and neuropathological
conditions. This review also addresses the multiple roles for
glutathione during mitochondrial inhibition or oxidative stress.
Protein aggregation and inclusions are hallmarks of a number of
neurodegenerative diseases. Recent evidence that links protein
aggregation to oxidative stress and mitochondrial dysfunction will also
be examined. Lastly, current therapies that target mitochondrial
dysfunction or oxidative stress are discussed.
PMID: 16115016
3. Disruption of mitochondrial redox circuitry in oxidative stress
Jones DP.
Chem Biol Interact. 2006 Oct 27;163(1-2):38-53.
The present review and commentary considers oxidative stress as a
disruption of mitochondrial redox circuitry rather than an imbalance of
oxidants and antioxidants. Mitochondria contain two types of redox
circuits, high-flux pathways that are central to mechanisms for ATP
production and low-flux pathways that utilize sulfur switches of
proteins for metabolic regulation and cell signaling. The superoxide
anion radical (hereafter termed "superoxide", O2*-), a well known free
radical product of the high-flux mitochondrial electron transfer chain,
provides a link between the high-flux and low-flux pathways. Disruption
of electron flow and increased superoxide production occurs due to
inhibition of electron transfer in the high-flux pathway, and this
creates aberrant "short-circuit" pathways between otherwise
non-interacting components. A hypothesis is presented that superoxide
is not merely a byproduct of electron transfer but rather is generated
by the mitochondrial respiratory apparatus to serve as a positive
signal to coordinate energy metabolism. Electron mediators such as free
Fe(3+) and redox-cycling agents, or potentially free radical scavenging
agents, could therefore cause oxidative stress by disrupting this
normal superoxide signal. Methods to map the regulatory redox circuitry
involving sulfur switches (e.g., redox-western blotting of
thioredoxin-2, redox proteomics) are briefly presented. Use of these
approaches to identify sites of disruption in the mitochondrial redox
circuitry can be expected to generate new strategies to prevent
toxicity and, in particular, promote efforts to re-establish proper
electron flow as a means to counteract pathologic effects of oxidative
stress.
PMID: 16970935
4. Mitochondrial oxidative stress: implications for cell death
Orrenius S, Gogvadze V, Zhivotovsky B.
Annu Rev Pharmacol Toxicol. 2007;47:143-83.
In addition to the established role of the mitochondria in energy
metabolism, regulation of cell death has emerged as a second major
function of these organelles. This seems to be intimately linked to
their generation of reactive oxygen species (ROS), which have been
implicated in mtDNA mutations, aging, and cell death. Mitochondrial
regulation of apoptosis occurs by mechanisms, which have been conserved
through evolution. Thus, many lethal agents target the mitochondria and
cause release of cytochrome c and other pro-apoptotic proteins into the
cytoplasm. Cytochrome c release is initiated by the dissociation of the
hemoprotein from its binding to the inner mitochondrial membrane.
Oxidation of cardiolipin reduces cytochrome c binding and increases the
level of soluble cytochrome c in the intermembrane space. Subsequent
release of the hemoprotein occurs by pore formation mediated by
pro-apoptotic Bcl-2 family proteins, or by Ca(2+) and ROS-triggered
mitochondrial permeability transition, although the latter pathway
might be more closely associated with necrosis. Taken together, these
findings have placed the mitochondria in the focus of current cell
death research.
PMID: 17029566
5. Mitochondria, oxidative stress and cell death
Ott M, Gogvadze V, Orrenius S, Zhivotovsky B.
Apoptosis. 2007 May;12(5):913-22.
In addition to the well-established role of the mitochondria in energy
metabolism, regulation of cell death has recently emerged as a second
major function of these organelles. This, in turn, seems to be
intimately linked to their role as the major intracellular source of
reactive oxygen species (ROS), which are mainly generated at Complex I
and III of the respiratory chain. Excessive ROS production can lead to
oxidation of macromolecules and has been implicated in mtDNA mutations,
ageing, and cell death. Mitochondria-generated ROS play an important
role in the release of cytochrome c and other pro-apoptotic proteins,
which can trigger caspase activation and apoptosis. Cytochrome c
release occurs by a two-step process that is initiated by the
dissociation of the hemoprotein from its binding to cardiolipin, which
anchors it to the inner mitochondrial membrane. Oxidation of
cardiolipin reduces cytochrome c binding and results in an increased
level of "free" cytochrome c in the intermembrane space. Conversely,
mitochondrial antioxidant enzymes protect from apoptosis. Hence, there
is accumulating evidence supporting a direct link between mitochondria,
oxidative stress and cell death.
PMID: 17453160
6. Introduction to oxidative stress and mitochondrial dysfunction
Mandelker L.
Vet Clin North Am Small Anim Pract. 2008 Jan;38(1):1-30.
Oxidative stress and mitochondrial dysfunction are discussed in this
article. Mitochondria are the major producers of free radicals and the
major target of oxidative damage. Oxidative stress is simply the
elevation of free radicals (reactive oxygen species/reactive nitrogen
species) found in cells that accumulate to higher than normal levels.
Excessive or inappropriate oxidative stress damages cells and tissues,
specifically mitochondria, cell membranes, DNA, proteins, and lipids.
PMID: 18249243
7. Chronic administration of methylphenidate activates mitochondrial respiratory chain in brain of young rats
Fagundes AO, Rezin GT, Zanette F, Grandi E, Assis LC, Dal-Pizzol F, Quevedo J, Streck EL.
Int J Dev Neurosci. 2007 Feb;25(1):47-51.
Methylphenidate is frequently prescribed for the treatment of attention
deficit/hyperactivity disorder. Psychostimulants can cause long-lasting
neurochemical and behavioral adaptations. The exact mechanisms
underlying its therapeutic and adverse effects are still not well
understood. In this context, it was previously demonstrated that
methylphenidate altered brain metabolic activity, evaluated by glucose
consumption. Most cell energy is obtained through oxidative
phosphorylation, in the mitochondrial respiratory chain. Tissues with
high energy demands, such as the brain, contain a large number of
mitochondria. In this work, our aim was to measure the activities of
mitochondrial respiratory chain complexes II and IV and succinate
dehydrogenase in cerebellum, prefrontal cortex, hippocampus, striatum,
and cerebral cortex of young rats (starting on 25th post-natal day and
finishing on 53rd post-natal day) chronically treated with
methylphenidate. Our results showed that mitochondrial respiratory
chain enzymes activities were increased by chronic administration of
this drug. Succinate dehydrogenase was activated in cerebellum,
prefrontal cortex and striatum, but did not change in hippocampus and
brain cortex. Complex II activity was increased in cerebellum and
prefrontal cortex and was not affected in hippocampus, striatum and
brain cortex. Finally, complex IV activity was increased in cerebellum,
hippocampus, striatum and brain cortex, and was not affected in
prefrontal cortex. These findings suggest that chronic exposure to
methylphenidate in young rats increases mitochondrial enzymes involved
in brain metabolism. Further research is being carried out in order to
better understand the effects of this drug on developing nervous system
and the potential consequences in adulthood resulting from early-life
drug exposure.
PMID: 17188451
8. Genes & Environment in ADHD
9. Etiologic Models in ADHD
10. Mitochondria and Pollutants including Thimerosal
11. Air Pollution and Mitochondria
12. Antibiotics and Mitochondria
13. Mitochondria dysfunction reviewed in:
Evidence of Mitochondrial Dysfunction in Autism and Implications for Treatment
Daniel A. Rossignol and J. Jeffrey Bradstreet
Am Journal Biochem Biotech 4(2): 208-217, 2008
http://www.scipub.org/fulltext/ajbb/ajbb42208-217.pdf
Classical mitochondrial diseases occur in a subset of individuals with
autism and are usually caused by genetic anomalies or mitochondrial
respiratory pathway deficits. However, in many cases of autism, there
is evidence of mitochondrial dysfunction (MtD) without the classic
features associated with mitochondrial disease. MtD appears to be more
common in autism and presents with less severe signs and symptoms. It
is not associated with discernable mitochondrial pathology in muscle
biopsy specimens despite objective evidence of lowered mitochondrial
functioning. Exposure to environ-mental toxins is the likely etiology
for MtD in autism. This dysfunction then contributes to a number of
diagnostic symptoms and comorbidities observed in autism including:
cognitive impairment, language deficits, abnormal energy metabolism,
chronic gastrointestinal problems, abnormalities in fatty acid
oxidation, and increased oxidative stress. MtD and oxidative stress may
also explain the high male to female ratio found in autism due to
increased male vulnerability to these dysfunctions. Biomarkers for
mitochondrial dysfunction have been identified, but seem widely
under-utilized despite available therapeutic interventions. Nutritional
supplementation to decrease oxidative stress along with factors to
improve reduced glutathione, as well as hyperbaric oxygen therapy
(HBOT) represent supported and rationale approaches. The underlying
pathophysiology and autistic symptoms of affected individuals would be
expected to either improve or cease worsening once effective treatment
for MtD is implemented.
14. Inter-Individual Variation in Detoxification: a preliminary miscellany
Additional topics will be added from time to time
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