Biochemical observations of mitochondrial dysfunction in autism
What is mitochondrial DNA?
Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA. This genetic material is known as mitochondrial DNA or mtDNA.
Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Each cell contains hundreds to thousands of mitochondria, which are located in the fluid that surrounds the nucleus (the cytoplasm). Mitochondria produce energy through a process called oxidative phosphorylation. This process uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell’s main energy source. A set of enzyme complexes, designated as complexes I-V, carry out oxidative phosphorylation within mitochondria.
In addition to energy production, mitochondria play a role in several other cellular activities. For example, mitochondria help regulate the self-destruction of cells (apoptosis). They are also necessary for the production of substances such as cholesterol and heme (a component of hemoglobin, the molecule that carries oxygen in the blood). Mitochondrial DNA contains 37 genes, all of which are essential for normal mitochondrial function. Thirteen of these genes provide instructions for making enzymes involved in oxidative phosphorylation. The remaining genes provide instructions for making molecules called transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), which are chemical cousins of DNA. These types of RNA help assemble protein building blocks (amino acids) into functioning proteins.
Biochemical observations of mitochondrial dysfunction in autism
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Common features in those with autism include: raised blood or serum lactate, regional disturbances in glucose uptake in the brain, particularly in the cortex, and reduced brain levels of high-energy phosphate compounds.These observations would suggest a mitochondrial energy disorder in the brain. Mitochondrial dysfunction may result from any of the following:
Impairment of mitochondrial fatty acid oxidation due to carnitine deficiency. Carnitine pumps fatty acids into the mitochondria. With the help of vitamins B6, C, and
niacin, the body produces carnitine from the amino acids lysine and methionine found in high quality protein. Adequate amounts are not thus formed so some carnitine must come from muscle and organ meats in the diet for it is not found in vegetables. Obviously, a low protein or a vegetarian diet would likely create a deficiency of this vital nutrient, and impair the mitochondrial function causing a loss of energy and a build up of triglycerides and fatty acids in the blood and cells.
The Cincinnati Children’s Hospital Medical Center’s Department of Enzymology has identified two patients with the "carbohydrate deficient glycoprotein syndrome" through alpha-1-antitrypsin phenotyping. The carbohydrate deficient glycoprotein in the serum of these patients produces a band on polyacrylamide gel isoelectric focusing that moves cathodally of the Z-band. In the area of carnitine deficiency, there is, for example, less than 5% of normal muscle carnitine concentration. After carnitine supplementation, patients unable to talk or walk, with hypotonic musculature and symptoms of autism, became able to walk with the help of a walker. They could stand alone for short periods, and they acquired an interest in their surroundings. The common findings of carnitine deficiency were an impaired ability to walk, muscular hypotonia, reduced muscle carnitine concentration, and an improvement in locomotion while on carnitine.
Cellular energy production itself produces free radicals that can damage cell structures, including the mitochondria, and ultimately lead to various diseases if the body’s natural antioxidant capacity is inadequate. Acylcarnitine and lipoic acid are both endogenous (naturally present in the body) antioxidants that have been shown to restore the mitochondrial function and reduce free radical damage. (Hagen TM et al., 1998; Lyckesfeldt J et al., 1998). Together with coenzyme Q10 and NADH, they work to maintain the function of the mitochondria.
It should be noted that not only fatty acids are needed, but glucose must be able to enter the cell to produce energy needed by the cell and by the muscles. Just as L-carnitine pumps in fatty acids, Alpha Lipoic Acid pumps in glucose. Its supplementation tends to overcome syndrome X, where the cells are resistant to glucose. This resistance produces unnaturally high blood levels of insulin and sugar.
Since the amino acid L–carnitine is frequently lacking in the autistic, this could predispose to heart problems and a lack of energy. The primary function of carnitine is to escort fatty acids into the mitochondrial furnace where the fat is burned to fuel ATP for energy. In this action it reduces blood levels of triglycerides and cholesterol dramatically, and aids weight loss. It boosts energy levels for those suffering from elevated blood sugar levels and kidney insufficiency. This reduces fatigue. Tests by Dr. Carl Pepine at the University of Florida showed that carnitine increases blood flow in the heart by 60%, and reduced vascular resistance 25%. It reduces heart arrhythmias by 58% to 90% in patients with chronic heart problems. He reported that patients were enabled to walk 80% farther before discomfort set in. Dr. A. Feller (1988) reported in the Journal of Nutrition that arrhythmias are usually a result of a carnitine deficiency. The heart is enabled to pump more blood, with fewer beats, and with less tendency toward oxygen deprivation. Vitamin E would be its ally in this for it enables muscles to function on 40% less oxygen. This would relieve angina and reduce risk of heart attack. A deficiency may result in chronic tiredness, fatigue, nausea, dizziness and anemia. Lysine is converted to carnitine, and carnitine increases Acetylcholine an important neurotransmitter. Autonomic system abnormalities can be caused by disturbances in Acetylcholine levels, known to be deficient in both autism and mercury poisoning.
L-carnitine (500 mg capsules twice daily on an empty stomach, or with a carbohydrate snack) reduced ketone, triglyceride (up to 40%), and cholesterol (up to 21%) levels, and increased HDL levels (up to 15%). The suggested use is 200 mg three times a day, increasing after one week to 400 mg three times daily, to improve brain energy levels. Basic L-carnitine may draw moisture and become unstable, and it is not the most bioavailable. While the citrate, lactate, and tartrate are good forms, the most effective form is L-carnitine fumarate. It is up to 9% more bioavailable. Carnitine will conserve calcium, magnesium, and potassium, and may reduce heart arrhythmias and fatigue—which will reduce risk of heart attack.
Due to increased fat burning, carnitine supplementation creates a significant need for caloric increase. If none is supplied there will likely be weight loss. It also generates increased free radicals that can severely damage cells unless additional antioxidants are supplied—particularly vitamins C and E and selenium. Additionally, lower than normal levels of certain essential fatty acids, such as cholesterol (needed as the precursor to many hormones) and triglycerides (a large proportion of the blood’s fatty substances) can be exacerbated by supplemental carnitine. One Mother says, "We lost our seizure control, and did not regain it until calories had been upped
significantly...Please, everyone, let’s consider very carefully the premise that carnitine supplementation creates a significant need for caloric increase." The level of fatty acids in the autistic child is an important factor because the endocrine system and its hormones, the brain and its neurotransmitters, the myelin sheath, and all the immune system components are derived from lipids (fats).
However, mitochondria cannot metabolize very long-chain, fatty acids (VLCFA) which many autistic have accumulated; so, if carnitine pumps additional ones into the cell, they can accumulate in the cells where they have toxic effects. Adrenoleukodystrophy (ALD) is a rare, fatal, degenerative disease caused by a build up of very long-chain, fatty acids (c22 to c28) that destroys the myelin (protective sheath) of the nerves. Canola oil is a very long-chain, fatty acid oil (c22). Inability to handle VLCFAs is almost universally true in autistic children, but is also seen in Alzheimer’s patients, chronic fatigue, and cardiovascular disease. The accumulation of VLCFAs inside the cell membrane represents defects in peroxisomal, beta-oxidation that is likely the result of hypothyroidism. Therefore, the toxic aspect so often described in autism may be defined clearly through examination of Red Blood Cell lipids with elevation of VLCFAs being a reflection of blocked detoxification mechanisms (that is, the Phase I liver enzymes are sluggish). These can be enhanced with milk thistle and other herbs mentioned herein. In some cases the VLCFA DHA is reduced. In that case supplementation of DHA has proven most helpful in relieving many symptoms of VLCFA disease.
Carnitine supplementation holds great promise, and it must be supplemented when Depakote™ is being used, but I think there are some things we must guard against. Additional carnitine will pump more fatty acids into the mitochondria to produce additional energy. It would help to know from a previous blood test that the triglycerides and cholesterol were normal or elevated. When using carnitine, to avoid creating a deficiency in fatty acids, we must supplement with Evening Primrose and cod-liver oils as outlined elsewhere in this paper, and ensure the child is getting enough calories for his size and activity. The wild card is the VLCFAs. To determine their status run the Red Blood Cell Lipid test. Symptoms of fatty acid deficiency would tend to be thirst, dry skin and hair, brittle nails, excess urination, dandruff, eczema, and rough skin. If these symptoms, or low triglyceride/cholesterol levels, or excess VLCFAs were present, I would not supplement carnitine, until these problems were being corrected. As I understand it, carnitine could lower the fatty acids and blood fats adversely, and could overload the cell with VLCFAs that it cannot burn. Look to the thyroid, do the iodine test, and if indicated, support the thyroid.
A second cause of mitochondrial energy disorder is inflammation associated with the release of excess nitric oxide. The herb Ginkgo Biloba selectively increases the release of nitric oxide synthase, the enzyme that reacts with arginine to produce nitric oxide. It should be avoided in this instance. Excess nitric oxide can cause uncoupling of oxidative phosphorylation as well as inhibiting the Krebs cycle enzyme, aconitase. This will result in organic acidemias, and low mitochondrial energy production. Lactic acidosis and carnitine deficiency in autistic patients suggest excessive nitric acid production in mitochondria (Lombard, 1998, Chigani, et al, 1999), and mercury may be a participant. Methyl mercury accumulates in the mitochondria, where it inhibits several mitochondrial enzymes, reduces ATP production and Ca2+ (calcium) buffering capacity, and disrupts mitochondrial respiration and oxidative phosphorylation (Atchison & Hare, 1994; Rajanna and Hobson, 1985; Faro et al., 1998). The behavior associated with excess NO production in the autist is maniacal laughter.
Neurological problems are among the most common and serious of mercury poisoning, and include memory loss, moodiness, depression, anger and sudden bursts of anger/rage, self-effacement, suicidal thoughts, lack of strength/force to resolve doubts or resist obsessions or compulsions. Mercury causes decreased lithium levels, which is a factor in neurological diseases such as depression and Alzheimer’s. Lithium protects brain cells against excess glutamate induced excitability and calcium influx, and low levels cause abnormal brain cell balance and neurological disturbances. Medical texts on neurology point out that chronic mercurialism is often misdiagnosed as dementia or neurosis or functional psychosis.
Mercury at extremely low levels interferes with formation of tubulin producing neurofibrillary tangles in the brain similar to those observed in Alzheimer’s patients with high levels of mercury in the brain. Mercury and the induced neurofibrillary tangles appear to produce a functional zinc deficiency in the AD sufferers, as well as causing reduced lithium levels. Mercury binds to hemoglobin in the red blood cell, and will reduce the amount of oxygen that can be carried in the blood—a major cause of Fatigue. Mercury at a level of 1 part per ten million will actively destroy the membrane of red blood cells. Mercury binds with cell membranes interfering with sodium and potassium enzyme functions, causing excess membrane permeability, especially in terms of the blood-brain barrier. Less than 1 ppm mercury in the blood stream can impair the blood-brain barrier. Mercury also blocks the immune function of magnesium and zinc. Exposure to mercury vapor causes decreased zinc and methionine availability, depresses rates of methylation (a bodily process of converting inorganic forms to organic forms, part of the detox process), and increases free radicals—all factors in increased susceptibility to chronic disease and to cancer. Mercury, especially organic mercury, causes accumulation of calcium into the cells, therefore, one does not want to take much calcium, and one wants to have a high ratio of magnesium to calcium, that is, keep magnesium up and calcium down to reduce the accumulative effects. Mercury also blocks the metabolic action of manganese, allowing an increased production of NO and the entry of calcium ions into cell.
Magnesium and manganese are the doorkeepers regulating the proper amount of calcium entering the cell. Mercury, if excreted in the urine, pulls out magnesium from the body, thus increasing the manganese relative to magnesium levels. Rarely is mercury excreted and most commonly it migrates to the brain where it can drive both brain toxicity and increases in manganese. In either case, increases in manganese relative to magnesium may increase measles viral mutations. Shifts in magnesium to manganese cations in the body can significantly enhance viral mutation rates by 6-10 fold.
The significance of this in your child’s life may be seen in the following: A group measured mercury levels in 15 preterm and 5 term infants before and after Hep B vaccination. According to the group, after-vaccination mercury levels in both preterm and term infants showed a significant increase. Mercury levels in the preterm infants were three times higher than in the term infants, and this was statistically significant, according to the team—Dr. Gregory V. Stajich from Mercer University, Atlanta, Georgia,
A recent study demonstrates that oral administration of N-acetylcysteine (NAC), a widely available and largely nontoxic amino acid derivative, produces a profound acceleration of urinary methyl mercury excretion in mice. Mice that received NAC in the drinking water (10 mg/ml) starting at 48 hr after methyl mercury administration excreted from 47 to 54% of the 203 Hg in urine over the subsequent 48 hr, as compared to 4-10% excretion in control animals. When NAC was given from the time of methyl mercury administration, it was even more effective at enhancing urinary methyl mercury excretion, and at lowering tissue mercury levels. In contrast, excretion of inorganic mercury was not affected by oral NAC administration. Three other nontoxic elements that readily bond to mercury rendering it less toxic and more easily excretable are Oxygen, Sulfur, and Selenium. Mercury binds strongly to selenium, a trace element that is needed for cellular health, depleting its stores. Latest research shows a conclusive connection between reduced levels of Selenium and increased risk of cancers.
A lack of selenium also affects the conversion of T4 thyroid hormone to T3. Stress reduces the conversion of T4 to the more active T3. Both cadmium and mercury inhibits the conversion of thyroxine (T4) to active T3. In a Chinese study, researchers found that selenium and vitamin E deficiency reduced blood levels of T3 by more than one-third. Vitamin E was thought to protect the T4/T3 conversion process. All myelination is controlled by T3. Free T3 regulates serotonin and melatonin metabolism. T3 controls serotonin uptake, binding to its receptors, so if there are serotonin problems, look to the thyroid. The active hormone T3 converts from T4, and to do this you need a specific ratio of zinc to copper of about 8:1. If you have had hair analysis and or fecal testing or blood tests you may know what your ratio is. If not, I would suggest finding out. Mercury (like in amalgam, and thimerosal in vaccines) will also cause hypothyroidism by interfering with selenoenzymes (Watanabe et al, 1999), and mercury competes and really messes up zinc absorption/utilization creating all kinds of effects throughout the body.
Defects in respiratory chain enzymes. Pyruvate Dehydrogenase or mitochondrial respiratory chain defects, that is, NAD, NADH, Coenzyme Q10, and cytochrome oxidase deficiency. Although we find a variety of autistic phenotypes to have associated mitochondrial abnormalities, the most common is nonspecific PDD, typically of a form that manifests language and cognitive regression or stagnation during the second year. Most surprising among multiplex families is that the biochemical and clinical markers of mitochondrial disease often segregate in an autosomal dominant manner (that is, genetically induced). Although no molecular lesion has yet been found in the autosomal dominant families, the biochemical findings are most consistent with abnormal mitochondrial complex I activity (that is NAD/NADH activity—WSL). Early and careful evaluation of autistic children for these more subtle mitochondrial disturbances may rescue them from more severe brain injury (Kelley, Richard, Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD). Note that the acetylaldehyde toxin given off by candida yeast inhibits the NAD/NADH exchange.
Excess glutamate exposure, a common and increasing source being MSG. Generally, autistic children show low glutamine, high glutamate readings. Plasma levels of glutamic acid and aspartic acid are elevated even as levels of glutamine and asparagine were low (Moreno-Fuenmayor et al, 1996). Mercury inhibits the uptake of glutamate, with consequent elevation of glutamate levels in the extracellular space (O’Carroll et al, 1995). Thimerosal enhances extracellular free arachidonate and reduces glutamate uptake (Volterra et al, 1992). Excessive glutamate is implicated in epileptiform activities (Scheyer, 1998; Chapman et al, 1996). Cells that are without oxygen may release excessive glutamate. Low oxygen is common in autistics. Children’s forming brains are four times more sensitive to neuro-excitotoxins. The lower the energy production of the cell, the more susceptible it is to excitotoxicity. Low magnesium levels (common in "our" children) can double free radical production and magnify their toxicity! The generation of increased levels of free radicals within the cell can activate the p53 tumor-suppressor gene triggering apoptosis (cell suicide). Excess glutamate can kill neurons by necrosis (by its allowing excess calcium into the cells) as well. Magnesium is the calcium regulator. Elevated plasma glutamate lowers cellular GSH by inhibiting cystine uptake.
Additionally, high levels of insulin inhibit an enzyme in the cell wall responsible for helping to regulate proper intracellular calcium balance. Since the interstitial fluid outside the cell usually contains a thousand times higher concentration of calcium than is normally present within the cell, this excess insulin response to our improper (high carbohydrate) diet simply opens the calcium floodgates into the cell by inhibiting this membrane enzyme. Mercury, and especially organic mercury, causes accumulation of calcium into the cells, therefore, one does not want to take much calcium, at least one wants to have a high ratio of Mg/Ca, that is, keep magnesium up and calcium down to reduce the accumulative effects—and supplement manganese. Otherwise, excessive calcium will enter the cells, impairing metabolism, producing cross-linkages and premature aging, and eventually producing dangerous arterial spasms. Manganese is a natural chelating agent when taken in the food supply or as a supplement. Manganese and magnesium will do everything a calcium channel blocker will do, but more naturally and effectively. There will be no excessive intracellular infiltration by calcium transporting through the cell membrane as long as manganese and magnesium are present.
Manganese works in a similar way to magnesium’s characteristic of displacing calcium ions. One of the keys to mercury’s effects on health may be its ability to block the functioning of manganese, a key mineral required for physiological reactions. New studies in humans and in the laboratory show that PCBs and mercury interact to cause harm at lower thresholds than either substance acting alone.
Though forced to remove MSG, baby formula today frequently utilizes caseinate that contains a high enough level of glutamate to endanger a newborn’s brain! These excitotoxic additives are hidden under the terms hydrolyzed vegetable protein, protein isolate, protein extracts, caseinate, and natural flavorings! Another damaging excitotoxin is Aspartame™ that has increased exponentially in all our foods. Some of the many aspartame toxicity symptoms reported include seizures, headaches, memory loss, tremors, convulsions, vision loss, nausea, dizziness, confusion, depression, irritability, anxiety attacks, personality changes, heart palpitations, chest pains, skin diseases, loss of blood sugar control, arthritic symptoms, weight gain (in some cases), fluid retention, and excessive thirst or urination. The phenylalanine in aspartame lowers the seizure threshold and depletes serotonin. Lowered serotonin triggers manic depression, panic attacks, anxiety, rage, mood swings, suicidal tendencies, etc. Clearly, regular exposure to a toxic substance such as formaldehyde may worsen, or in some cases contribute to the development of chronic diseases. Other excitotoxins include fluoride, aluminum, iron overload, and organophosphate pesticides and herbicides.
It would appear that the pathology of autism is one of immune dysregulation, with associated food intolerance, and opportunistic infection that triggers excessive production of the inflammatory cytokines and nitric oxide leading eventually to neural mitochondrial inhibition. Dr Rosemary Waring tells us that the excess cytokines reduces available sulfates also.
Nutrients that may improve the mitochondrial function include, magnesium, Coenzyme Q10, N-acetylcarnitine, N-acetylcysteine, vitamins B1, B2, niacin/niacinamide, folic acid, NAD (Nicotinamide Adenine Dinucleotide), alpha-ketoglutarate, and antioxidants such as vitamin E, C, alpha lipoic acid, manganese, and selenium. Supplementation of glutathione has improved skill with numbers and fine motor skills. Oral glutathione is expensive, and not well assimilated, though of benefit to the gut. If you use it, take it with some vitamin C that will improve its assimilation by up to 20%. Kirkman has a lotion for transdermal application that will overcome the absorption problem. Use both. Where possible, help the body produce its own supply.
Biochemical observations in Autism
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Last edited by cellsalts; 6th March 2008 at 03:15 AM. Reason: Typos
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