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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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The mitochondria are tiny organelles that are often overlooked in the treatment of disease. Yet, mitochondrial dysfunction drives the development of – or worsens the symptoms of – some of the most devastating diseases of modern times, including cancer, cardiovascular disease, Alzheimer's, Parkinson's, autism, and diabetes, as well as many other conditions that don't at first glance seem related to the mitochondria such as autism, bipolar disorder, or osteoarthritis. Ironically, not only are the mitochondria often ignored by many conventional doctors in the treatment of disease, the same patients suffering from mitochondrial-related diseases are given drugs that impair mitochondrial function.
The volumes of research about the mitochondria and mitochondrial dysfunction indicate that what is now known about the mitochondria extends far beyond what we learned in basic biology. An abundance of fascinating research continues to spotlight the role that mitochondrial dysfunction plays in most – if not all – diseases. Mitochondrial dysfunction's role in disease is particularly concerning, given that the mitochondria of the modern human are subjected to some assaults never experienced by people who lived before the early 1900s. Therefore, it's critical to become familiar with these tiny organelles, to learn how their dysfunction can contribute to disease, and to discover the best ways to protect the mitochondria and ensure that they are functioning optimally.

How Mitochondria Function: A Brief Recap
Before we discuss mitochondrial dysfunction, it is important to review the way in which mitochondria function. It starts with glycolysis, which occurs outside the mitochondria. Glycolysis converts glucose into pyruvate, which is then converted into acetyl-CoA. The citric acid cycle (also known as the Krebs cycle) then takes over inside the mitochondria to convert the acetyl-CoA into the reduced form of nicotinamide adenine dinucleotide (NADH) and the reduced form of flavin adenine dinucleotide (FADH2), which are important in a process known as oxidative phosphorylation (OXPHOS).
Through their oxidation and breakdown, NADH and FADH2 help fuel OXPHOS, which is responsible for producing the energy that powers cells. In OXPHOS, electron donors transfer electrons to electron acceptors by using electron transport chains. Energy is released when an electron is transferred to an acceptor such as oxygen. The mitochondria, using the enzyme ATP synthase, use the energy produced in the electron transport chain to manufacture adenosine triphosphate (ATP) from adenosine diphosphate (ADP). ATP is to our bodies what gasoline is to our cars. We could not function without it and any defects in ATP production often result in fatigue. Metabolic processes that use ATP as an energy source convert it back into its precursors. Therefore, ATP is continually recycled.
The energy produced by OXPHOS causes protons (particles with positive electric charge) to be transported across the inner mitochondrial membrane. This creates a gradient that produces additional energy.
There are five complexes in the electron transport chain:
•    Complex I (NADH dehydrogenase)Complex I is an enzyme that catalyzes the two-electron oxidation of the reduced form of nicotinamide adenine dinucleotide (NADH) by coenzyme Q10 (ubiquinone). During Complex I, ubiquinone also is reduced to ubiquinol, which results in the generation of energy by the creation of a proton gradient.
•    During Complex II (succinate dehydrogenase)reactions, succinate is oxidized into fumarate and ubiquinone is reduced. This process does not produce as much energy as Complex I, and is unable to create a proton gradient.
•    Complex III (cytochrome c reductase) results in the oxidation of one molecule of ubiquinol and the reduction of two molecules of cytochrome c, a protein responsible for transferring electrons. This reaction very efficiently transfers protons across the mitochondrial membrane, creating a proton gradient, thereby assisting with energy production.
•    Complex IV (cytochrome c oxidase) is an enzyme that oversees the last step in the electron transport chain. During this reaction, electrons are transported to oxygen, which is reduced to water, and protons are transported across the mitochondrial membrane.
•    Complex V (ATP synthase) is the last enzyme utilized in oxidative phosphorylation. By tapping into the energy reservoir generated by the proton gradient across a membrane, ATP synthase assists with the creation of ATP from ADP and phosphate.
Oxidative phosphorylation is the most efficient ATP producer. For example, for every 1 glucose molecule oxidized, only 2 ATP molecules are generated by glycolysis, whereas the electron transport chain can generate between 30 to 36 ATP molecules.
Oxidative phosphorylation is a critical part of normal metabolism, but it has a dark side as well. The process produces reactive oxygen species (ROS) – for example, superoxide and hydrogen peroxide – which can result in cellular damage and lead to disease and accelerated aging.1

Are GM Foods Harming the Mitochondria?
The mitochondria are subjected to a number of modern-day insults, including toxins. Although there are many toxins that impair mitochondrial function, one of the most prevalent is glyphosate (used in Roundup). Because genetically modified (GM) foods are engineered to be resistant to glyphosate, they're slathered with this herbicide.
This is particularly disturbing given that every year, Americans are eating their body weight in GM foods, according to an analysis by the Environmental Working Group.2 Additionally, near the Mississippi Delta farmlands, glyphosate and its degradation product aminomethylphosphonic acid (AMPA) were found in 75% or more of air and rain samples in 2007.3 This indicates that glyphosate is extremely prevalent in agricultural areas.
Glyphosate is especially toxic to the mitochondria when it is combined with surfactants or adjuvants, primarily in the formulation known commercially as Roundup. These surfactants or adjuvants are claimed to be inert, but research paints a different picture. Researchers have shown that adjuvants in glyphosate-based herbicides were as much as 10 times more harmful than glyphosate itself.4 One group of researchers found Roundup to be 125 times more toxic than glyphosate alone.5
Strong evidence indicates that surfactants or adjuvants disrupt cell membranes and initiate toxic changes to the mitochondria. Studies have shown that adjuvants have been found to exert their toxic effects through interfering with mitochondrial respiration.3 One study of rat liver mitochondria found that Roundup suppressed mitochondrial Complexes II and III. Treatment of the mitochondria with the herbicide formulation resulted in uncoupling of oxidative phosphorylation, an effect not seen when the mitochondria were treated with glyphosate alone.6
Another study investigated the effects of Roundup or glyphosate alone on human buccal epithelial cells of the mouth in order to determine the effects of inhaling the herbicide. Roundup caused cellular membrane damage and mitochondrial dysfunction at levels greater than 40 mg/liter after 20 minutes. Glyphosate alone also was toxic to cellular membranes, but at double the concentration of Roundup used. Both Roundup and glyphosate caused DNA damage, even at lower doses, although Roundup was more toxic than glyphosate alone. Toxicity with Roundup was noted even after short exposure to concentrations 450 times more diluted than that sprayed on agricultural crops.7

Chronic Stress and the Mitochondria
Another modern-day cause of mitochondrial dysfunction is chronic stress. Although our ancient ancestors faced short-term stresses, such as an attack by a saber-tooth tiger, today we deal with chronic, ongoing stressors that take a toll on mitochondrial health. 
Researchers have reported that chronic stress results in the production of too much nitric oxide, which could suppress mitochondrial respiratory chain function and trigger oxidative stress.8 Chronic stress may also cause the mitochondria to produce an overwhelming amount of free radicals, which neurons aren't able to neutralize, causing mitochondrial dysfunction and neuronal cell death.9
Chronic stress can deplete the mitochondria's ability to produce energy. The brain is activated by stress, which can produce alterations in the brain's structure and function known as neuronal plasticity. The mitochondria must fuel these changes by producing additional energy. When the mitochondria are working the way they are supposed to, they are able to produce the energy demanded by stress-caused neuronal plasticity, protecting against the development of depression. However, when mitochondrial function is weakened, the brain's energy stores that are used up during stress are not replenished. This compromises neuronal plasticity and may increase the likelihood of developing depression.10

Fructose and Mitochondria
In the US, high-fructose corn syrup was introduced into the food supply in the 1970s. One of the mechanisms by which high-fructose corn syrup may induce type 2 diabetes and obesity is through its ability to cause mitochondrial dysfunction. Rats that were exposed to a high-fructose diet during gestation and lactation had impaired brain mitochondrial function in their old age and decreased mitochondrial phosphorylation efficiency.11
Fructose metabolism produces intermediary metabolites that overwhelm mitochondrial capacity in the liver, which can result in the development of hepatic insulin resistance. Additionally, fructose triggers formation of excessive reactive oxygen species, which can overwhelm the mitochondria.12

Some Medications Pose Another Threat
Many medications can cause mitochondrial dysfunction, which has emerged as the mechanism behind many side effects and toxicities of drugs. Some medications can directly affect electron transport chain complexes or damage electron transport chain components. Plus, medications can suppress enzymes necessary for mitochondrial function. In addition, some medications can trigger free radical production, depleting levels of antioxidants such as glutathione. Furthermore, pharmaceuticals can interfere with the absorption of nutrients that the mitochondrial electron transport chain complexes need for proper function.13
Many medications for angina, arrhythmia, depression, anxiety, high cholesterol (including statins), cancer, dementia, diabetes, HIV/AIDs, epilepsy, and Parkinson's can cause mitochondrial dysfunction. The antibiotics tetracycline and antimycin A, some barbiturates and anxiety medications, and anesthetics such as bupivacaine, lidocaine, and propofol are all toxic to the mitochondria. Even something as commonplace as aspirin and acetaminophen (Tylenol) can impair mitochondrial functioning.13

Epigenetic Involvement
The mitochondrial damage induced by the factors mentioned above can be transferred to children and grandchildren through epigenetics, heritable changes in gene expression that are not caused by changes in the DNA sequence.14,15 The epigenetic modification of mitochondrial DNA may be responsible for the pathogenesis of many diseases.16

The Consequences of Mitochondrial Dysfunction
Mitochondrial dysfunction plays a role in the majority of today's most burdensome diseases – including aging itself.

Aging and the Mitochondria
The mitochondria contain members of gene family referred to as sirtuins, which are involved in longevity. Sirtuins are the conductors of the anti-aging orchestra. These genes control genetic, biochemical, and cellular pathways involved in aging.17,18 Amplifying the expression of these genes is thought to increase longevity.19,20
The mitochondria contain three of the seven mammalian sirtuins, including SIRT3 and SIRT4.21 Mitochondrial sirtuins may enhance longevity through mimicking caloric restriction, which protects against age-related disease and dysfunction, including cancer initiation.22-26
Beyond the sirtuins, an abundance of scientific evidence shows a strong connection between aging and mitochondrial dysfunction.27-30 This evidence suggests that as mitochondria are exposed to a cumulative amount of reactive oxygen species and mitochondrial DNA damage, the burden becomes too much to bear, ultimately resulting in decreased lifespan.26 With age, mitochondrial oxidative phosphorylation becomes less efficient.31

Cancer is one of many diseases associated with mitochondrial dysfunction. The risk of developing cancer rises after age 50, which lends support to a potential link between mitochondrial processes involved in longevity and cancer development.26,32,33 Furthermore, mitochondrial dysfunction in cancer cells is frequently noted in studies and coincides with abnormal cellular metabolism.34,35 Researchers have found strong support for the likelihood that mitochondrial dysfunction plays an important role in cell transformation and carcinogenesis.26

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