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From the Townsend Letter
June 2015

Mitochondria: Overlooking These Small Organelles Can Have Huge Clinical Consequences in Treating Virtually Every Disease
by Chris D. Meletis, ND, and Kimberly Wilkes
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Autistic Spectrum Disorders (ASD)
Mitochondrial dysfunction is well known to occur in autistic spectrum disorder.36 The origin of this mitochondrial damage could be partially genetic. However, mitochondrial mutations are found in only 23% of ASD children diagnosed with mitochondrial dysfunction. Therefore, environmental causes such as exposure to heavy metals, exhaust fumes, polychlorinated biphenyls, or pesticides may be more important than genetic factors.37 The oxidative stress caused by exposure to these toxins may serve as the link between mitochondria dysregulation and ASD.
Endogenous insults such as elevated pro-inflammatory cytokines resulting from an activated immune system could also damage the mitochondria in ASD patients.38-40
Other evidence of the presence of mitochondrial dysfunction in ASD patients is the fact that genes involved in the electron transport chain are downregulated (decreased Complex I, III, IV, and V). Genes involved in the citric acid cycle are also downregulated. Furthermore, mitochondrial DNA damage also has been noted in ASD patients.41-43

Mental Disorders
Mitochondrial dysfunction is an underappreciated component of various mental disorders. Bipolar patients experience reduced levels of Complex I of the electron transport chain.44 Patients suffering from major depression also have abnormalities in Complex I.45 Similarly, researchers have noted a significant decrease in Complex I activity in schizophrenia patients along with a drop in CoQ10 levels.46 Mitochondrial abnormalities also have been noted in subjects with obsessive-compulsive disorder.47

Cardiovascular Concerns
Mitochondrial dysfunction is a key player in age-related damage to the heart. The heart has a high metabolic demand and contains a large number of mitochondria.  Because ROS is produced in the mitochondria through oxidative phosphorylation, the heart is particularly vulnerable to oxidative damage.31
Other evidence for mitochondrial dysfunction's association with cardiovascular disease includes the existence of mitochondrial dysregulation and mtDNA mutations in atherosclerotic plaques.48-51
According to one group of researchers, "Development of novel therapeutic approaches for mitochondrial rejuvenation and attenuation of mitochondrial oxidative stress holds promise for reducing cardiovascular mortality in an aging population."31
Mitochondrial dysfunction has been associated with the metabolic syndrome (a cluster of risk factors for cardiovascular disease) providing another reason why mitochondrial abnormalities may damage the heart.52-56

Type 2 Diabetes
Diabetes is marked by mitochondrial dysfunction and high oxidative stress levels.57 Persistently high blood sugar levels harm both mitochondria and mitochondrial DNA.58 Diabetic patients often experience downregulation of Complex I and/or IV and type 2 diabetes occurs side by side with some diseases related directly to mitochondrial dysfunction such as the genetic diseases Fanconi anemia and Werner syndrome.59-65

Neurodegenerative Diseases
Studies strongly suggest that mitochondria abnormalities may be linked to the development of several neurodegenerative diseases such as Parkinson's disease, Alzheimer's, Friedreich's ataxia, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease.8 Rat models of Parkinson's disease indicate that reactive oxygen species interfere with mitochondrial processes.65 Researchers have found that mitochondrial abnormalities caused by amyloid-beta occur early in Alzheimer's disease.66-72

Other Diseases Linked to Mitochondrial Dysfunction
In terms of diseases related to mitochondrial dysfunction, what we've discussed in this article so far is just the tip of the iceberg. For example, mtDNA damage has been noted in osteoarthritis along with downregulated Complexes I, II, and III, and 17 upregulated and 9 downregulated genes.73-75 Furthermore, in autoimmune diseases antimitochondrial autoantibodies (AMA) can damage the mitochondria.78 Autoimmune diseases associated with mitochondrial dysfunction include vitiligo, systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, primary biliary cirrhosis, and psoriasis.76
Additionally, researchers have attributed the damage done by obstructive sleep apnea (OSA) to mitochondrial dysfunction. In OSA patients there is a decrease in mtDNA copy number, which is linked to oxidative stress and inflammation.77
Other diseases related to mitochondrial dysfunction include cataracts, fibromyalgia, and non-alcoholic fatty liver disease.76

The Hormonal Link
When supporting optimal hormonal health amongst patients, it is essential to consider the mitochondrial health and function of the target endocrine tissues being treated. Fueling the target mitochondrial cells can dramatically augment therapeutic outcomes. This is because there is an intricate interplay between hormones and mitochondria.77-85 Hormones originate in the mitochondria where cholesterol is converted to pregnenolone, the precursor to all steroid hormones.78,79 The mitochondrial electron transport chain also plays a role in producing testosterone in the Leydig cells.80 Furthermore, receptors for estrogens, androgens, and thyroid hormones are located in the mitochondria.81,82 Estrogens and androgens also are able to shield the mitochondria from damage and estrogen is involved in many aspects of mitochondrial function and biogenesis, including oxidative phosphorylation.83-86

Diagnosing Mitochondrial Dysfunction
Along with clinical observations, an organic acid test is often used to diagnose mitochondrial dysfunction. Organic acids are produced as a result of the breakdown of proteins, carbohydrates, and fats. These acids serve as intermediates in the citric acid (Krebs) cycle.
The presence or elevation of specific organic acids can serve as a marker for mitochondrial abnormalities or indicate exposure to toxins that may harm the mitochondria. For example, 4-hydroxybenzoic acid and 4-hydroxyhippuric acid are metabolites of parabens, toxic compounds found in lotions, cosmetics, other toiletries, and even food.87,88 Parabens may impair oxidative phosphorylation, resulting in mitochondrial dysfunction.89 An organic acid test can determine if 4-hydroxybenzoic acid and 4-hydroxyhippuric acid are elevated.
Another example is the organic acid adipic acid (adipate). If the value is elevated it can indicate functional deficiency of carnitine. A deficiency of carnitine can stop long chain fatty acids from entering the mitochondria. This results in insufficient fatty acid oxidation. Organic acid tests also can measure a marker of CoQ10 production.
When interpreting organic acid test results, it is important to be familiar with all the nuances, because some foods and drugs as well as fasting can affect the results.90
Functional micronutrient testing also is important, because the pathways critical for ATP production need to be fueled by key nutrients. A deficiency in these nutrients can compromise mitochondrial health.

Clinical Considerations in Treating Mitochondrial Dysfunction
Because mitochondrial dysfunction has emerged as a key player in a host of different diseases, it makes sense to include a mitochondrial support component in wellness regimens.
From a lifestyle perspective, a ketogenic diet may enhance mitochondrial health in children with autistic spectrum disorder and epilepsy. A ketogenic diet is a high-fat diet with enough protein for growth but not enough carbohydrates for metabolic needs. This type of diet causes the body to use fat as its main source of fuel. A ketogenic diet has been shown to improve various aspects of mitochondrial function during in vitro, in vivo, and human studies.91-95 However, one problem with the ketogenic diet is that it is low in vegetables. The antioxidants in vegetables protect against excess reactive oxygen species generated by mitochondrial dysfunction, hence demanding consideration of supplemental antioxidant protection when consuming a ketogenic diet.
Research indicates moderate exercise also is critical to mitochondrial health. For example, in one mouse model of non-alcoholic steatohepatitis, mitochondrial abnormalities in the liver disappeared after the animals underwent endurance exercise.96

Fueling the Mitochondria
A number of the components required for oxidative phosphorylation need to be frequently replaced. This can be accomplished with supplementation of key nutrients such as L-carnitine, alpha-lipoic acid, coenzyme Q10, creatine monohydrate, and N-acetylcysteine (NAC), which have all been shown to be of benefit.97
Mitochondrial bioenergetic enzymes require alpha-lipoic acid, a critical cofactor. In rodent and cell culture studies, alpha-lipoic acid has been found to restore mitochondrial biogenesis, to reduce mitochondrial deformation and intracellular ROS production, and to increase intracellular ATP synthesis and mitochondrial DNA numbers.98,99
One randomized, double-blind clinical trial that used a combination of creatine monohydrate, coenzyme Q10, and alpha-lipoic acid lowered markers of oxidative stress in people with mitochondrial cytopathies while creatine monohydrate used alone in patients with mitochondrial encephalomyopathies enhanced aerobic oxidative function of the mitochondria.100,101
L-carnitine also is important to mitochondrial health because it helps transfer long-chain fatty acids from the cytoplasm of the cell to the mitochondria. During carnitine deficiency, there are less fatty acids available for energy production, resulting in symptoms such as myalgia and muscle weakness.102 It's therefore not surprising that acetyl-L-carnitine (ALC), which is created from acetylation of carnitine in the mitochondria, is a powerful mitochondrial rejuvenator. When paired with alpha-lipoic acid in a nonalcoholic fatty liver mouse model, ALC enhanced the content and size of the mitochondria in the liver.103 ALC supplementation also promoted the formation of new mitochondria in the livers of old rats, which helped reduce oxidative stress.104
Another component of a mitochondrial rejuvenation regimen is the glutathione precursor N-acetylcysteine, researched for its ability to enhance mitochondrial health. In one study of rats with spinal cord injuries, NAC improved mitochondrial bioenergetics and maintained mitochondrial glutathione levels near normal.105
Supplementing with citric acid cycle metabolites such as malate, succinate, and alpha-ketoglutarate can also be of benefit.106

Other Mitochondrial Rejuvenators
New studies are showing several other natural agents may have mitochondrial-restoring effects. Evidence is mounting that resveratrol can improve mitochondrial activity. In cells from patients with early onset Parkinson's disease, resveratrol enhanced mitochondrial oxidative function, which researchers believe is due to a decrease of oxidative stress and increased mitochondrial biogenesis. Resveratrol increased Complex I and citrate synthase activities, basal oxygen consumption, and mitochondrial ATP production.107

In other studies, resveratrol prevented mitochondrial dysfunction in a rat model of diabetic cardiomyopathy and increased cell survival after traumatic brain injury, in part by protecting the mitochondria.108,109
Surprisingly, glucosamine also emerged as a possible mitochondrial protector when a study published in 2014 showed that glucosamine extends the lifespan of both the nematode Caenorhabditis elegans and aging mice in part by enhancing mitochondrial biogenesis.110
Other nutrients shown to enhance mitochondrial function include quercetin, green tea, and omega-3 fatty acids.111-114
In treating any health condition and improving overall foundational well-being, we can't forget to look at the proverbial "Energizer bunny" batteries of the trillions of cells that comprise the human frame. Mitochondrial dysfunction is the driving force behind the development or symptom severity in many diseases. Given the widespread involvement the mitochondria have in disease, incorporating nutrients that fuel mitochondrial pathways into any wellness-oriented supplement regimen is key to restoring whole body health. Due to the role hormones play in mitochondrial health – and vice versa – nourishing the mitochondria during hormone replacement therapy also is advised. Bottom line: unfueled cells are destined to underperform.

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