for Generation Rescue
by Teresa Binstock
ADHD & Mitochondria
Introduction: Elevated oxidative stress alters mitochondria function (2-6). Several studies have linked ADHD with markers of elevated oxidative stress (1). A recent study in rats found that methylphenidate improves physiological markers related to mitochondria. (7). Increasing evidence documents that AD and ADHD are associated with environmental pollutants known to adversely affect mitochondria (8-12).
Whether induced by pollutants, illness, or predisposing alleles (10-14), elevated oxidative stress and its effects upon mitochondria may be etiologically significant in some and perhaps many cases of AD and ADHD. Furthermore, reducing excessive oxidative stress and treating mitochondria dysfunction - especially in the ongoing presence of pollutants - may be beneficial for some individuals (1, 10-12). The relationships and citations presented in this section merit research which includes clinical trials regarding AD, ADHD, elevated oxidative stress, mitochondria dysfunction, and related treatments.
1. ADHD & Oxidative Stress
2. Role of mitochondrial DNA in toxic responses to oxidative stress
Van Houten B, Woshner V, Santos JH.
DNA Repair (Amst). 2006 Feb 3;5(2):145-52.
Mitochondria are at the crossroads of several crucial cellular activities including: adenosine triphosphate (ATP) generation via oxidative phosphorylation; the biosynthesis of heme, pyrimidines and steroids; calcium and iron homeostasis and programmed cell death (apoptosis). Mitochondria also produce considerable quantities of superoxide and hydrogen peroxide (H2O2) that in conjunction with its large iron stores can lead to a witch's brew of reactive intermediates capable of damaging macromolecules. Mitochondrial DNA (mtDNA) represents a critical target for such oxidative damage. Once damaged, mtDNA can amplify oxidative stress by decreased expression of critical proteins important for electron transport leading to a vicious cycle of reactive oxygen species (ROS) and organellar dysregulation that eventually trigger apoptosis. Oxidative stress is associated with many human disorders including: cancer, cardiovascular disease, diabetes mellitus, liver disease and neurodegenerative disease. This article reviews the evidence that oxidative damage to mtDNA can culminate in cell death and thus represents an important target for therapeutic intervention in a number of human diseases.
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.
3. Disruption of mitochondrial redox circuitry in oxidative stress
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.
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.
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.
6. Introduction to oxidative stress and mitochondrial dysfunction
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.
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.
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
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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