MitoQ®: A Highly Bioavailable, Mitochondria-Targeted Form of Coenzyme Q10

MitoQ®: A Highly Bioavailable, Mitochondria-Targeted Form of Coenzyme Q10

by Chris D. Meletis, ND, Susanne Bennett, DC, and Kimberly Wilkes

Tiny organelles known as mito­chondria are the body’s equivalent of the batteries that power electrical devices. In other words, they are responsible for charging cells through the production of adenosine triphosphate (ATP), the energy molecule produced via the mitochondria’s electron transport chain. Any factor that impairs mitochondrial function and disrupts the production of ATP can lead to fatigue, pain and inflammation as well as a significant number of diseases. For example, aging,1-4 chronic stress,5,6 certain pharmaceutical drugs,7 ingesting high-fructose corn syrup,8 environmental toxins such as heavy metals9 and air pollution,10 even the herbicides sprayed on food11,12 have all been found to impair mitochondrial function. In fact, in today’s world, the mitochondria have a lot going against them.

The antioxidant coenzyme Q10 (CoQ10) is well known for its role in mitochondrial function. The overproduction of reactive oxygen species (ROS) by mitochondria is responsible for mitochondrial impairment and plays a major role in many diseases. Mitochondrial damage can be mitigated by improving mitochondrial antioxidant capacity through supplementing with ROS scavenger CoQ10, as it plays a critical role in the energy-producing electron transport chain. Known for its mitochondrial-enhancing properties, CoQ10 has been shown to lower mortality and increase exercise capacity in heart failure patients,13 diminish the frequency, duration, and severity of migraines,14 reduce wrinkles and improve smoothness of skin,15 and improve endothelial function and muscle recovery after strenuous exercise.16 CoQ10 is designed to sit in the inner mitochondrial membrane and does not cross cellular or mitochondrial membranes easily. For that reason, mitochondria manufacture CoQ10 inside the inner membrane and this is why the effectiveness of exogenous CoQ10 is significantly limited by its inability to reach the mitochondria.

In this article, we will discuss the role of CoQ10 in supporting mitochondrial function in various diseases with a special emphasis on a new mitochondria-targeted form of CoQ10 known as MitoQ (mitoquinol). Drs. Meletis and Bennett use this form of CoQ10 in their clinical practices, with much success.

Enhancing the Bioavailability of CoQ10

Because of its lipophilic properties, large molecular weight, and differences in its gastrointestinal permeability, CoQ10 has low oral bioavailability and only a small amount of oral CoQ10 finds its way to the circulatory system.17 Intracellular delivery is also a challenge and only a small percentage of the absorbed CoQ10 is available to the mitochondria.17 An analysis of several studies indicates that high doses of CoQ10 supplementation for a prolonged period of time are needed to elevate CoQ10 tissue levels.18 Additionally, the increase of CoQ10 that occurs after supplementation varies in different tissues.18

Many methods have been investi­gated to optimize CoQ10’s ability to enter tissues and mitochondria including reducing particle size, creating emulsification and phospholipid delivery systems, with limited success.17 MitoQ researchers finally achieved success in enhancing the delivery of CoQ10 into the mitochondria when they attached the ubiquinol form of CoQ10 to the lipophilic triphenylphosphonium cation, which allowed CoQ10 to enter into the mitochondria driven by the large mitochondrial membrane potential.19

This combination of ubiquinol and the triphenylphosphonium cation, known as mitoquinol, or MitoQ for short, is positively charged. Through an electrical gradient, MitoQ is attracted to the negatively charged interior of the cell, passing through the cell’s plasma membrane and ultimately penetrating the mitochondria’s double membrane. Lipophilic cations like triphenylphosphonium are easily able to penetrate lipid bilayers because they possess a charge that is distributed over a large surface region and the potential gradient allows them to accumulate in the mitochondrial matrix.20,21

MitoQ is transported rapidly into isolated mitochondria. Inside the mitochondria virtually all of the acquired MitoQ is adsorbed to the matrix surface of the inner membrane.22 This ability of MitoQ to enter the inner membrane of the mitochondria substantially improves CoQ10’s antioxidant capacity.22 MitoQ accumulates inside the mitochondria at concentrations up to a thousandfold greater than outside the cell.23 MitoQ is especially effective at delivering CoQ10 into tissues with high-energy needs where greater numbers of mitochondria are concentrated including neurons, cardiac muscle, and the liver and kidneys.22,23

Unlike many other forms of CoQ10, MitoQ is water soluble and demonstrates optimal oral bioavailability. Peak plasma levels are achieved in less than an hour.24 MitoQ is able to quickly penetrate all biological membranes, including the blood-brain barrier.25

The effects of MitoQ are probably attributed to accumulation of the ubiquinol form of CoQ10.26 After the ubiquinol form of MitoQ quenches a free radical, it is oxidized to ubiquinone. Soon after, Complex II recycles the ubiquinone back to ubiquinol, which is a more powerful antioxidant.26 Ubiquinol is highly effective at suppressing lipid peroxidation in phospholipid bilayers.27 Due to its recycling back to ubiquinol, MitoQ is especially effective against lipid peroxidation but can also reduce peroxynitrite and superoxide radicals.26

Potential Applications for Mitochondria-Targeted CoQ10

MitoQ has been extensively evaluated in preclinical studies and several human trials were conducted, with more on the way. The following is a brief review of the evidence for MitoQ’s effectiveness.

Liver Health

Hepatocytes (liver cells) have a high concentration of mitochondria and therefore benefit from antioxidant protection. One of the first clinical trials to be conducted on MitoQ investigated its effects in patients with the hepatitis C virus (HCV).28 Increased oxidative stress and the ensuing mitochondrial damage are mechanisms responsible for the liver injury that occurs in chronic HCV infection. Inhibiting mitochondrial oxidative damage may therefore be beneficial. Consequently, researchers conducted a phase II study to determine the effect of MitoQ on serum aminotransferases and HCV RNA levels in patients with HCV. The study authors randomized 30 HCV patients who either did not respond to standard therapy or were unsuitable for standard-of-care to receive MitoQ (40 mg or 80 mg) or placebo once daily for 28 days. Patients receiving either dose of MitoQ experienced pronounced declines in absolute and percentage changes in serum alanine transaminase (ALT) from baseline to treatment day 28. ALT is a significant indicator of liver damage and inflammation. MitoQ did not affect HCV load.

MitoQ has also been studied for its supportive role in cirrhosis. In this disease, activated hepatic stellate cells (HSC) are involved in increasing intrahepatic vascular resistance and the development of portal hypertension.29 Cirrhosis is also associated with elevated reactive oxygen species in the liver, which may explain why antioxidants lower portal pressure.29 Because much of this increased ROS production originates in the mitochondria, researchers tested MitoQ on HSC from human livers, as well as on liver cells from control and cirrhotic rats.29 The researchers also conducted an in vivo experiment in rats in which the effects of 5 mg/kg/day of MitoQ for two weeks on oxidative stress, systemic and hepatic hemodynamics, liver fibrosis, HSC phenotype, and liver inflammation was compared to a control compound.29 MitoQ inhibited the activity of human and rat HSC. Furthermore, in the rat model, MitoQ reduced hepatic oxidative stress, improved the HSC phenotype, decreased intrahepatic vascular resistance, and suppressed liver fibrosis. These effects were accompanied by a pronounced decline in portal pressure without changes in arterial pressure.

Fibromyalgia and Chronic Fatigue Syndrome

Fibromyalgia is a disorder character­ized by widespread pain and tenderness along with other symptoms including fatigue, cognitive problems, and poor sleep. Approximately 2% to 8% of the population suffers from fibromyalgia.30 Myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are similar disorders to fibromyalgia and are characterized by malaise after exertion and unexplained, chronic fatigue. Scientists investigated the effects of MitoQ on 100 patients with fibromyalgia, CFS, or ME.31 The fibromyalgia patients taking MitoQ experienced significant declines in pain scores (up to 33%) while no change was observed in the placebo group. Furthermore, patients given MitoQ experienced a 13% increase in working memory. CFS/ME patients given MitoQ did not experience notable effects in a double blind trial, but significant improvements in pain, energy, sleep quality, and mental clarity were observed in a separate open-label arm of the experiment.31

Cognitive and Neurological Health

Alzheimer’s disease is the most common neurodegenerative disease and an important cause of dementia among elderly individuals.25 Research indicates that mitochondrial impairment and oxidative stress are involved in Alzheimer’s disease progression.25 Researchers studied whether MitoQ can suppress pathology similar to Alzheimer’s in mouse cortical neurons in cell culture, and in a triple transgenic mouse model of Alzheimer’s disease.25 In the cortical neurons, MitoQ diminished the neurotoxicity caused by amyloid beta (peptides that accumulate in Alzheimer’s-affected brains), stopped the elevated production of reactive species, and decreased the loss of mitochondrial membrane potential. MitoQ given to mice for five months stopped the development of Alzheimer’s-like pathologies such as cognitive decline, oxidative stress, Aβ accumulation, astrogliosis, synaptic loss, and caspase activation in the brain.

MitoQ also has been studied in Parkinson’s disease, a chronic neurodegenerative disorder associated with neuronal mitochondrial dysfunction and low concentrations of the neurotransmitter dopamine. In mice, mesencephalic neuronal cells, and cultured dopaminergic cells exposed to toxins, MitoQ prevented neurotoxicity.32 In an in vitro model of Parkinson’s disease, MitoQ inhibited mitochondrial fragmentation due to oxidative stress.33 A phase II, double-blind study of MitoQ versus a placebo in 128 Parkinson’s patients did not demonstrate any effect of MitoQ on disease progression.34 This was likely due to the commencement of therapy when the neuronal injury was already too extensive to achieve any benefit from use of a neuroprotective agent. However, the study did demonstrate the excellent safety and tolerability of long-term use of MitoQ.

Maintaining Healthy Weight

Animal studies suggest MitoQ can protect against the effects of a high-fat diet. Mice prone to obesity that were given MitoQ in the drinking water and then fed a high-fat diet experienced a marked decline in total body mass and fat mass compared to mice fed a normal-fat diet.35 Mice given MitoQ and fed a high-fat diet also ate less food. Furthermore, MitoQ reduced fatty liver related oxidative damage.35

In another study by the same researchers, a dose of 500 μmol/L dose of MitoQ given to already obese mice caused the animals to drop too much weight and drink too little water so the researchers cut the dose in half.36 In this study, MitoQ had modest anti-obesity benefits. Primarily, MitoQ resulted in a robust decline in plasma leptin, an important marker of fat mass.

Diabetes and Metabolic Syndrome

Mitochondrial dysfunction is associated with the development or progression of metabolic syndrome, a cluster of risk factors for cardiovascular disease including high blood pressure, abdominal obesity, high blood sugar, and elevated low high-density lipoprotein cholesterol (HDL-C) levels. Researchers studied the effects of MitoQ on muscle lipid profile alterations and mitochondrial function in rats fed a diet prone to develop obesity.37 The study authors divided 24 young male rats to receive a high-fat diet, a high-fat diet with MitoQ, or a placebo. The high-fat diet triggered the development of obesity, hepatic enlargement, and glucose intolerance, features of the metabolic syndrome. MitoQ supplementation suppressed the increase in body weight and decreased the increase in fat tissue and liver weights in the animals fed a high-fat diet. It also partially reversed glucose intolerance. The high-fat diet caused increased triglyceride accumulation and important alterations in the muscle phospholipid classes and in the fatty acid composition of total muscle lipid. A decrease in mitochondrial respiration accompanied these changes. However, MitoQ supplementation stopped the lipid alterations and restored mitochondrial respiration.

In another study assessing the effects of MitoQ on leukocytes from patients with type 2 diabetes mellitus, MitoQ demonstrated anti-inflammatory and antioxidant abilities, including inhibiting ROS generation, decreasing interactions between leukocytes and the lining of blood vessels known as the endothelium, and inhibiting the inflammatory marker tumor necrosis factor-alpha (TNFα).38

Anti-Aging Effects

Oxidative stress is implicated in much of the cellular and tissue damage that occurs during aging. MitoQ may therefore be a useful agent in middle-aged and elderly individuals. Its anti-aging application was demonstrated in a recent study where MitoQ resulted in a pronounced inhibition of telomere shortening in human fibroblasts.39 Telomeres are the protective caps on the ends of chromosomes and a reduction in telomere length is associated with aging. MitoQ treatment also was associated with an average 40% increase in the replicative lifespan of the cells.39

MitoQ has also been studied for its effects on age-related endothelial dys­function. Mitochondrial dysfunc­tion is a major source of the oxidative stress implicated in arterial endothelial dysfunction. Endothelium-dependent dilation of arteries is reduced in old mice.40 However, MitoQ supplementation completely restored endothelium-dependent dilation in older mice by improving nitric oxide bio­availability.40 MitoQ-induced im­prove­ments in endothelial function were related to normalization of age-associated oxidative stress and increases in indicators of vascular mitochondrial health, such as antioxidant status. During aging there is an increase in the susceptibility of arterial endothelium to acute mitochondrial damage. MitoQ reversed this susceptibility.40

Cardiovascular

Oxidative stress originates when there is an imbalance between the production of ROS and antioxidant synthesis. Oxidative stress is an important factor in the development of cardiovascular diseases such as atherosclerosis, ischemic heart disease, heart failure, stroke, and hypertension.41 Mitochondrial dysfunction can lead to the excessive production of ROS and is often involved in the origin of cardiovascular disease.41,42

MitoQ is therefore a logical choice to support cardiovascular health. In animal models of heart transplantation and heart attacks, MitoQ has been found to protect against ischemia-reperfusion damage, injury that occurs when oxygen is introduced back into oxygen-starved arteries.43,44

In stroke-prone spontaneously hypertensive rats, a combination of MitoQ and low-dose losartan (a blood pressure medication) resulted in synergistic benefit.45 The combination markedly reduced development of hypertension and left ventricular hypertrophy. Furthermore, in cell culture, MitoQ directly suppressed hypertrophy of heart muscle cells (cardiomyocytes) from rats.45

Another beneficial application for MitoQ may be for individuals taking cholesterol-lowering drugs.46 Cholesterol and other isoprenoids produced via the same pathway are required by CoQ10 to attach it to the inner membrane of the mitochondria.46 Therefore, cholesterol-lowering drugs reduce CoQ10’s availability to the mitochondria, and MitoQ could replenish the mitochondria’s supply of CoQ10 in people on these medications.46

The utility of MitoQ for cardiovascular protection was recently investigated in humans, in a study of older adults (males, 60-79) at Colorado University.47 Alongside other benefits the results showed those taking MitoQ for six weeks experienced an average of 48% improvement in arterial function.

Conclusion

CoQ10 is an antioxidant that is well-known for the important part it plays in mitochondrial function. However, supplemental CoQ10 does not easily penetrate the mitochondrial membrane. A new form of this nutrient known as MitoQ combines the ubiquinol form of CoQ10 with the lipophilic triphenylphosphonium cation, significantly increasing its ability to enter into the mitochondria. In human trials, this mitochondria-targeted nutrient has been shown to support liver health in patients with HCV, improve arterial function in older adults, and reduce pain and improve memory in individuals with fibromyalgia. Additional human trials are being conducted or are in the planning stage. Animal studies also suggest MitoQ may enhance brain health, support a healthy weight, suppress components of metabolic syndrome, have anti-aging effects, and be involved in cardiovascular health.

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References

  1. Singh KK. Mitochondrial dysfunction is a common phenotype in aging and cancer. Ann N Y Acad Sci. 2004;1019:260-4.
  2. Afanas’Ev IB. Mechanism of superoxide-mediated damage relevance to mitochondrial aging. Ann N Y Acad Sci. 2004;1019:343-5.
  3. Berneburg M, et al. Repair of mitochondrial DNA in aging and carcinogenesis. Photochem Photobiol Sci. 2006;5(2):190-8.
  4. Singh KK. Mitochondria damage checkpoint, aging, and cancer. Ann N Y Acad Sci. 2006;1067:182-90.
  5. Madrigal JL, et al. Glutathione depletion, lipid peroxidation and mitochondrial dysfunction are induced by chronic stress in rat brain. Neuropsychopharmacology. 2001 Apr;24(4):420-9.
  6. Beal MF. Mitochondria, free radicals, and neurodegeneration. Curr Opin Neurobiol. 1996 Oct;6(5):661-6.
  7. Neustadt J and Pieczenik SR. Medication-induced mitochondrial damage and disease. Mol Nutr Food Res. 2008;52:780-8.
  8. Mortensen OH, et al. Developmental programming by high fructose decreases phosphorylation efficiency in aging offspring brain mitochondria, correlating with enhanced UCP5 expression. J Cereb Blood Flow Metab. 2014 Jul;34(7):1205-11.
  9. Belyaeva EA, et al. Mitochondrial Electron Transport Chain in Heavy Metal-Induced Neurotoxicity: Effects of Cadmium, Mercury, and Copper. ScientificWorldJournal. 2012;2012:136063.
  10. Zhaobin Xu, et al. Ambient particulate air pollution induces oxidative stress and alterations of mitochondria and gene expression in brown and white adipose tissues. Part Fibre Toxicol. 2011;8:20.
  11. Majewski MS, et al. Pesticides in Mississippi air and rain: a comparison between 1995 and 2007. Environ Toxicol Chem. 2014 Jun;33(6):1283-93.
  12. Peixoto F. Comparative effects of the Roundup and glyphosate on mitochondrial oxidative phosphorylation. Chemosphere. 2005 Dec;61(8):1115-22.
  13. Lei L, Liu Y. Efficacy of coenzyme Q10 in patients with cardiac failure: a meta-analysis of clinical trials. BMC Cardiovasc Disord. 2017 Jul 24;17(1):196.
  14. Shoeibi A, et al. Effectiveness of coenzyme Q10 in prophylactic treatment of migraine headache: an open-label, add-on, controlled trial. Acta Neurol Belg. 2017 Mar;117(1):103-9.
  15. Žmitek K, et al. The effect of dietary intake of coenzyme Q10 on skin parameters and condition: Results of a randomised, placebo-controlled, double-blind study. Biofactors. 2017 Jan 2;43(1):132-40.
  16. Sarmiento A, et al. Short-term ubiquinol supplementation reduces oxidative stress associated with strenuous exercise in healthy adults: A randomized trial. Biofactors. 2016 Nov 12;42(6):612-22.
  17. Zaki NM. Strategies for oral delivery and mitochondrial targeting of CoQ10. Drug Deliv. 2016 Jul;23(6):1868-81.
  18. Kamzalov S, et al. Coenzyme Q Intake Elevates the Mitochondrial and Tissue Levels of Coenzyme Q and α-Tocopherol in Young Mice. J Nutr. 2003 Oct 1;133(10):3175-80.
  19. Kelso GF, et al. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J Biol Chem. 2001 Feb 16;276(7):4588-96.
  20. Feliceazzone G, et al. Determination of the proton electrochemical gradient across biological membranes. Current Topics in Bioenergetics. 1984;13:1-77.
  21. Ross MF, et al. Lipophilic triphenylphosphonium cations as tools in mitochondrial bioenergetics and free radical biology. Biochemistry (Mosc). 2005 Feb;70(2):222-30.
  22. Murphy MP. Targeting lipophilic cations to mitochondria. Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):1028-31.
  23. Ross MF, et al. Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells. Biochem J. 2008 May 1;411(3):633-45.
  24. Antipodean Pharmaceuticals, Inc. A dose ranging study of the pharmacokinetics and safety of mitoquinone administration in healthy adult volunteers. 25 January 2006.
  25. McManus MJ, et al. The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease. J Neurosci. 2011 Nov 2;31(44):15703-15.
  26. James AM, et al. Interactions of mitochondria-targeted and untargeted ubiquinones with the mitochondrial respiratory chain and reactive oxygen species. Implications for the use of exogenous ubiquinones as therapies and experimental tools. J Biol Chem. 2005 Jun 3;280(22):21295-312.
  27. James AM, et al. Antioxidant and prooxidant properties of mitochondrial Coenzyme Q. Arch Biochem Biophys. 2004 Mar 1;423(1):47-56.
  28. Gane EJ, et al. The mitochondria-targeted antioxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients. Liver Int. 2010 Aug;30(7):1019-26.
  29. Vilaseca M, et al. Mitochondria-targeted antioxidant mitoquinone deactivates human and rat hepatic stellate cells and reduces portal hypertension in cirrhotic rats. Liver Int. 2017 Jul;37(7):1002-12.
  30. Clauw DJ. Fibromyalgia: a clinical review. JAMA. 2014 Apr 16;311(15):1547-55.
  31. Johnson C, Grant J. The influence of Mitoq on symptoms and cognition in fibromyalgia, myalgic encephalomyelitis and chronic fatigue. https://www.researchgate.net/publication/306032775_The_influence_of_Mitoq_on_symptoms_and_cognition_in_fibromyalgia_myalgic_encephalomyelitis_and_chronic_fatigue Accessed August 21, 2017.
  32. Ghosh A, et al. Neuroprotection by a mitochondria-targeted drug in a Parkinson’s disease model. Free Radic Biol Med. 2010 Dec 1;49(11):1674-84.
  33. Solesio ME, et al. The mitochondria-targeted anti-oxidant MitoQ reduces aspects of mitochondrial fission in the 6-OHDA cell model of Parkinson’s disease. Biochim Biophys Acta. 2013 Jan;1832(1):174-82.
  34. Snow BJ, et al. A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson’s disease. Mov Disord. 2010 Aug 15;25(11):1670-4.
  35. Fink BD, et al. A mitochondrial-targeted coenzyme q analog prevents weight gain and ameliorates hepatic dysfunction in high-fat-fed mice. J Pharmacol Exp Ther. 2014 Dec;351(3):699-708.
  36. Fink BD, et al. Metabolic effects of a mitochondrial-targeted coenzyme Q analog in high fat fed obese mice. Pharmacol Res Perspect. 2017 Mar 10;5(2):e00301.
  37. Coudray C, et al. A mitochondrial-targeted ubiquinone modulates muscle lipid profile and improves mitochondrial respiration in obesogenic diet-fed rats. Br J Nutr. 2016 Apr 14;115(7):1155-66.
  38. Escribano-Lopez I, et al. The mitochondria-targeted antioxidant MitoQ modulates oxidative stress, inflammation and leukocyte-endothelium interactions in leukocytes isolated from type 2 diabetic patients. Redox Biol. 2016 Dec;10:200-5.
  39. Saretzki G, et al. MitoQ counteracts telomere shortening and elongates lifespan of fibroblasts under mild oxidative stress. Aging Cell. 2003 Apr;2(2):141-3.
  40. Gioscia-Ryan RA, et al. Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice. J Physiol. 2014 Jun 15;592(12):2549-61.
  41. Subramanian S, et al. Mitochondrially targeted antioxidants for the treatment of cardiovascular diseases. Recent Pat Cardiovasc Drug Discov. 2010 Jan;5(1):54-65.
  42. Milagros Rocha M, Victor VM. Targeting antioxidants to mitochondria and cardiovascular diseases: the effects of mitoquinone. Med Sci Monit. 2007 Jul;13(7):RA132-45.
  43. Dare AJ, et al. The mitochondria-targeted anti-oxidant MitoQ decreases ischemia-reperfusion injury in a murine syngeneic heart transplant model. J Heart Lung Transplant. 2015 Nov;34(11):1471-80.
  44. Adlam VJ, et al. Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury. ASEB J. 2005 Jul;19(9):1088-95.
  45. McLachlan J, et al. Combined therapeutic benefit of mitochondria-targeted antioxidant, MitoQ10, and angiotensin receptor blocker, losartan, on cardiovascular function. J Hypertens. 2014 Mar;32(3):555-64.
  46. Barbato JC. Have no fear, MitoQ10 is here. Hypertension. 2009 Aug;54(2):222-3.
  47. Rossman MJ, et al. MitoQ supplementation improves vascular endothelial function in healthy late middle-aged and older adults. Research presented at the Cardiovascular Aging: New Frontiers and Old Friends August 11-14 2017.
Posted by DrMeletis in Articles, Mitochondrial Health, Townsend
The Vagus Nerve’s Role in Chronic Fatigue, Depression, Obesity, and Other Common Diseases

The Vagus Nerve’s Role in Chronic Fatigue, Depression, Obesity, and Other Common Diseases

by Chris D. Meletis, ND, and Kimberly Wilkes

Many common diseases and disorders that plague us today have their roots in a nerve that the average person doesn’t know exists. It’s called the vagus nerve, and it plays a role in everything from obesity to heart health to kidney disease and depression. In fact, new research is emerging that infections in this nerve are involved in chronic fatigue syndrome.

Vagus is the Latin word for “wandering,” because this nerve extends throughout much of the body. The largest nerve in the autonomic nervous system, the vagus nerve begins in the medulla oblongata of the brainstem and then extends into every chest and abdominal organ from the neck to the transverse colon with the exception of the adrenal glands. This nerve also regulates some skeletal muscles. The vagus nerve involves both afferent neurons (sensory neurons) and efferent neurons (motor neurons), although the majority of its neurons (65% to 80%) are afferent neurons, which send sensory information about the status of our organs to the central nervous system.1 Efferent vagus nerve fibers supply the pharynx and back of the throat with nerves and initiate the gag reflex.

It was once thought that the vagus nerve affected only the stomach and heart, but now we know that it casts a much wider net in the body and that it has a considerable number of functions far beyond what was initially thought. In this article, we will discuss the many ways that the vagus nerve affects your health.

Chronic Fatigue Syndrome

It has long been suspected that viral infections may trigger chronic fatigue syndrome and that an ongoing immune response may lead to the debilitating fatigue associated with the syndrome. Functional medicine has long held that it is individual susceptibility of the host that creates the ecology for a given disease state to manifest. I have long held that the vagal nerve plays a role in chronic fatigue and countless other common ailments, which has been also postulated by scientist Michael B. VanElzakker. He presents a convincing argument that infection of the vagus nerve may be responsible for this disorder.2

When an infection lands on immune cells’ radar, they release pro-inflammatory cytokines, which are detected by receptors of the vagus nerve. The receptors signal the brain to initiate fatigue, fever, myalgia, depression, and other symptoms of a cold, flu, or viral or bacterial infection. VanElzakker contends that chronic fatigue symptoms are a more prolonged version of those normal sickness symptoms and that chronic fatigue symptoms are triggered when any virus or bacterium infects the vagal ganglia (a structure containing nerve cells). These virus- or bacteria-activated cells can assault the vagus nerve with proteins known as pro-inflammatory cytokines and other substances that signal the development of sickness symptoms. This hypothesis proposed that any infection of the vagus nerve can lead to chronic fatigue syndrome and that not just one virus or bacterium is responsible for chronic fatigue but rather that any pathogen can cause the disorder.

Depression, ADHD, and Other Cognitive Disorders

The vagus nerve is involved in cognitive health and emotional well-being. Vagal nerve stimulation is commonly used to treat drug-resistant epilepsy and depression.3 It also is used to eliminate fear and anxiety and is involved in our response to traumatic events.4 The vagus nerve determines how likely you are to be affected emotionally by a trauma long after it has concluded.5

A marker of increased emotional sensitivity to trauma is reduced heart rate variability, an indicator that the vagal nerve is not working properly. The vagus nerve slows the heart rate during safe, nontraumatic conditions. However, in response to threats, the heart-rate inhibiting effect of the vagus nerve stops, allowing the sympathetic nervous system to mobilize defense responses and heart rate increases. Ongoing exposure to conflict and threats may impair vagal system function over time. This results in a reduced ability of the body to adapt to stressful events.

Heart rate variability that operates at a higher level during nonstressful times is thought to be a sign that a person has a healthy ability to regulate emotions and cope with stress. A vagus nerve that is operating optimally is thought to reflect psychological flexibility, emotional self-regulation, and positive adaptation. On the other hand, low resting state heart rate variability is a sign of a reduced ability to control emotional responses to stressful events. Reduced resting heart rate variability is linked to greater trauma exposure and mental disorder. It also is associated with worse physical health, PTSD, depression and anxiety, and aggression and anger. People who have reduced resting heart rate variability also are more vulnerable to stress and it takes them longer to recover from a stressful experience.5 In one study of 45 people with post-traumatic stress disorder (PTSD), depression, and intermittent explosive disorder and 29 controls who did not have these disorders, resting heart rate variability was significantly lower in the people with the mental disorders compared with the controls.5

The vagus nerve also plays a role in reducing aggressive behavior in attention-deficit hyperactivity disorder (ADHD). In a rodent model of ADHD, a substance that reduced aggression no longer worked when the vagus nerve was removed.6 In ADHD, the autonomic nervous system does not work properly, resulting in poor control of the heart. Cardiac vagal control is lower in children with untreated ADHD compared with healthy controls.7 Children with ADHD experience reduced cardiac vagal control reactivity when performing tasks involving self-regulation and regulation of emotions.

The means by which the vagus nerve affects mental health may be due to its involvement in the gut–brain axis. The vagus nerve is one of the primary means of communication between the gut and the brain.8 The microbiota may interact with the vagus nerve to send signals to the brain.9

Weight Management and Food Intake

In the gastrointestinal tract, afferent vagus nerves control food intake. However, in obesity, GI vagal responses to stimuli are modified leading to a shift away from satiety toward increased food intake.10 Vagal pathways that aren’t operating properly are involved in the development of obesity and the inability to lose weight already gained. Many studies have shown that the gut microbiota is involved in weight maintenance. The gut microbiota assists in the production of short chain fatty acids (SCFAs), which in turn results in the production of substances that can then act on afferent vagus nerves to increase satiety. Specifically, the SCFA butyrate can directly activate vagal afferent nerves in the small intestine.10

Gut hormones activate vagal afferent neurons, the primary neural pathway by which information about ingested nutrients reaches the central nervous system (CNS) to play a role in both GI function and satiety. Vagal afferent neurons can also become resistant to the hormone leptin, which regulates appetite. Furthermore, in a rodent model, a high-fat diet produced changes in the gut microbiota and this imbalance resulted in gut inflammation and “leaky gut.”11 Through toxins escaping into the bloodstream, this led to changes in the function of vagal neurons.

Another advantage of the vagus nerve is that it can counteract the inflammation that occurs as a person gains weight. The vagus nerve also has the ability to reduce insulin resistance. Researchers fed rats either a high-fat diet or a high-fat diet together with vagus nerve stimulation.12 The rats exposed to only a high-fat diet developed a number of damaging effects in the brain, including insulin resistance, oxidative stress, inflammation, and the cell death known as apoptosis, which all lead to cognitive decline. However, the group fed a high-fat diet together with vagus nerve stimulation had an improvement in peripheral and brain insulin sensitivity as well as reduced brain mitochondrial dysfunction and cell apoptosis. Vagus nerve stimulation also enhanced cognitive function.

Conversely, an overly active vagus nerve can play a role in bulimia nervosa. Increases in vagal afferent activity are linked to binge-eating and vomiting in this condition.13 Inhibiting vagal afferent activity in subjects with severe bulimia nervosa results in a rapid and pronounced decline in binge-eating and vomiting compared with controls as well as reduced depressive symptoms.13

Cardiovascular

Cardiovascular disease interferes with the regulatory function of the autonomic nervous system. The two branches of the autonomic nervous system are the parasympathetic and sympathetic nervous systems. These must remain in balance in order to properly regulate the heart’s electromechanical function, resulting in the ideal cardiac output after exposure to a number of environmental and metabolic stressors. Diseases such as chronic heart failure and hypertension are linked to autonomic imbalances characterized by increased sympathetic drive and reduced parasympathetic activity. Vagus nerve stimulation normalizes autonomic function and improves cardiovascular function and heart failure symptoms.14

In obese, insulin-resistant rats fed a high-fat diet, vagus nerve stimulation resulted in a pronounced decline in plasma insulin, total cholesterol, triglycerides, LDL, and visceral fat. Vagus nerve stimulation also significantly reduced blood pressure, improved heart rate variability and left ventricular function, and enhanced cardiac mitochondrial function.15 Vagus nerve stimulation also has reduced blood pressure in a rat model of hypertension.16

Furthermore, research has shown that stimulation of the vagus nerve is beneficial in stroke. Recombinant tissue-type plasminogen activator is used within 4.5 hours of a stroke. This results in a rapid reintroduction of cerebral blood flow. While this has its advantages it also leads to an excessive inflammatory response that worsens ischemic injury, which can be harmful to the patient. In animal models of endotoxemia (toxins in the blood), stimulation of vagus nerve efferents results in a significant decline in systemic levels of pro-inflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 1 beta (IL-1β), and the DNA-binding protein, high-mobility group box 1 (HMGB-1).17

Stimulation of the vagus nerve also is neuroprotective leading to a decrease in infarct volume during the acute phase of ischemic stroke.17 Researchers induce strokes in rodents by blocking the middle cerebral artery. When vagal nerve stimulation is begun within 30 minutes after blocking the artery, infarct volume is reduced by nearly 50%, and there is an improvement in neurological score.18

In hypertensive rats prone to developing strokes, vagus nerve stimulation prevents the endothelial dysfunction caused by high blood pressure. It also prevents the aortic stiffening that would otherwise occur in these animals.19 Researchers believe that the anti-inflammatory actions of vagus nerve stimulation may be responsible for these beneficial effects.

Immune System Support

The vagus nerve’s regulation of inflammation is involved in immune system activity. During infection or injury, sensory input triggered by inflammation travels through the afferent vagus nerve to the brainstem, from which efferent nerves send signals that terminate in the spleen and other tissues.20 This assists in communication between immune cells, indicating that the vagus nerve is important for optimal functioning of the immune system.

Roemheld Syndrome

This disorder is characterized by arrhythmia (irregular heart beat), tachycardia (rapid heart rate), gastrointestinal complaints, intestinal gas, panic attacks, confusion, anxiety, depression, blood pressure fluctuations, dizziness and balance issues, lightheadedness, fainting, nausea, and tinnitus. In this syndrome, problems in the gastrointestinal tract or abdomen trigger heart-related symptoms.

While researching the symptoms in the 1920s to 1940s, Dr. Ludwig Roemheld discovered that the vagus nerve plays an important role in the syndrome, since this nerve is connected to the brain, heart, lungs, and GI tract.21 Changes in the gut can affect the vagus nerve, causing heart rate to slow. This leads to the activation of autonomic reflexes, which increase blood pressure and heart rate.

Other Conditions Related to Vagus Nerve Function

Optimal functioning of the vagus nerve is involved in many other aspects of health. Stimulation of the vagus nerve reduces trigeminal pain, and the vagus nerve may be involved in a rare type of trigeminal neuralgia known as vagoglossopharyngeal neuralgia.22,23 Vagus nerve stimulation also reduces migraine and cluster headaches.22,24 Additionally, vagus nerve stimulation has prevented acute kidney injury in rodent studies.25 Another way in which the vagus nerve affects health is its important involvement in the reflex relaxation of the lower esophageal sphincter, which has implications for gastroesophageal reflux disease (GERD).26,27

Another interesting aspect of the vagus nerve’s involvement in health is its ability to trigger the cough reflex.28 Furthermore, inflammatory conditions respond well to vagus nerve stimulation, due to this nerve’s anti-inflammatory abilities.29 Researchers believe that vagus nerve stimulation could be used successfully in inflammatory bowel diseases, irritable bowel syndrome, postoperative ileus, and rheumatoid arthritis.29

Natural Ways to Support Vagus Nerve Function

Acupuncture is one means by which the vagus nerve can be stimulated. The reason why acupuncture produces so many beneficial effects may be because it can increase the vagus nerve’s ability to regulate inflammatory responses in internal organs.30 The autonomic nervous system is involved in acupuncture’s benefits because it is the connection between external sensory inputs and internal organ responses. Signals from many acupuncture points may travel to the vagus nerve, where they affect the function of the autonomic nervous system.30 Studies also have shown that tai chi can influence vagus nerve function.31 Heart rate variability increases immediately after both young and old men perform tai chi.32

As mentioned earlier in this article, heart rate variability is a marker of vagus nerve function. Studies have shown that a number of supplements can improve heart rate variability and vagus nerve function. For example, researchers investigated the effects of L-citrulline on resting heart rate variability and blood pressure in obese postmenopausal women.33 The researchers randomly divided the women to receive either L-citrulline or a placebo. Supplementation with L-citrulline resulted in improvements in heart rate variability and blood pressure as well as a significant increase in vagal tone. Beetroot juice is another supplement that increases heart rate variability at rest and during aerobic exercise in addition to reducing systolic blood pressure in human subjects.34 In subjects who consumed a multivitamin-mineral preparation together with 300 mg guarana, heart rate variability remained stable, whereas in participants consuming either caffeine or a placebo, heart rate variability significantly declined.35

Omega-3 fatty acids are another nutrient shown to affect vagus nerve functioning. Higher concentrations of the omega-3 fatty acid docosahexaenoic acid (DHA) are associated with lower blood pressure and resting heart rate and higher heart rate variability.36 Another study found that higher intakes of omega-3 fatty acids were linked to higher heart rate variability during sleep-time.37 A review of the medical literature showed that short-term fish-oil supplementation enhanced vagal tone and thus improved heart rate variability.38

Conclusion

Optimal functioning of the vagus nerve can drive many aspects of our health. Chronic fatigue, depression, ADHD, obesity, cardiovascular conditions, and impaired immunity are all related to reduced function of the vagus nerve. Stimulating the vagus nerve has relieved trigeminal nerve pain and migraine and cluster headaches and prevented acute kidney injury. Through its inflammation-dampening effect, vagus nerve stimulation could also be used successfully in inflammatory bowel diseases, irritable bowel syndrome, postoperative ileus, and rheumatoid arthritis. Acupuncture and tai chi can improve vagus nerve activity; and L-citrulline, beetroot juice, multivitamins, guarana, and omega-3 fatty acids have all been shown to increase heart rate variability, a marker of optimal vagus nerve function.

Download Article:  The Vagus Nerve’s Role in Chronic Fatigue, Depression, Obesity, and Other Common Diseases

Notes

  1. Puledda F, Goadsby PJ. Current approaches to neuromodulation in primary headaches: focus on vagal nerve and sphenopalatine ganglion stimulation. Curr Pain Headache Rep. 2016 Jul;20(7):47.
  2. VanElzakker MB. Chronic fatigue syndrome from vagus nerve infection: A psychoneuroimmunological hypothesis. Med Hypotheses. September 2013. 81(3):414–423.
  3. Rossi S et al. The heart side of brain neuromodulation. Philos Trans A Math Phys Eng Sci. 2016 May 13;374(2067).
  4. Burger AM et al. The effects of transcutaneous vagus nerve stimulation on conditioned fear extinction in humans. Neurobiol Learn Mem. 2016 Jul;132:49–56.
  5. Liddell BJ et al. Heart rate variability and the relationship between trauma exposure age, and psychopathology in a post-conflict setting. BMC Psychiatry. 2016 May 10;16(1):133.
  6. Hida H. The importance of vagus nerve afferent in the formation of emotions in attention-deficit hyperactivity disorder model rat. [In Japanese.] Brain Nerve. 2016 Jun;68(6):633–639.
  7. Rash JA, Aguirre-Camacho A. Attention-deficit hyperactivity disorder and cardiac vagal control: a systematic review. Atten Defic Hyperact Disord. 2012 Dec;4(4):167–177.
  8. Dinan TG, Cryan JF. The impact of gut microbiota on brain and behaviour: implications for psychiatry. Curr Opin Clin Nutr Metab Care. 2015 Nov;18(6):552–558.
  9. Sherwin E et al. may the force be with you: the light and dark sides of the microbiota-gut-brain axis in neuropsychiatry. CNS Drugs. Epub 2016 Jul 14.
  10. Kentish SJ, Page AJ. The role of gastrointestinal vagal afferent fibres in obesity. J Physiol. 2015 Feb 15;593(4):775–786.
  11. De Lartigue G et al. Vagal afferent neurons in high fat diet-induced obesity; intestinal microflora, gut inflammation and cholecystokinin. Physiol Behav. 2011 Nov 30;105(1):100–105.
  12. Chunchai T et al. Vagus nerve stimulation exerts the neuroprotective effects in obese-insulin resistant rats, leading to the improvement of cognitive function. Sci Rep. 2016 May 26;6:26866.
  13. Faris PL et al. Evidence for a vagal pathophysiology for bulimia nervosa and the accompanying depressive symptoms. J Affect Disord. 2006 May;92(1):79–90.
  14. Lee SW et al. Chronic cyclic vagus nerve stimulation has beneficial electrophysiological effects on healthy hearts in the absence of autonomic imbalance. Physiol Rep. 2016 May;4(9).
  15. Samniang B et al. Vagus nerve stimulation improves cardiac function by preventing mitochondrial dysfunction in obese-insulin resistant rats. Sci Rep. 2016 Feb 1;6:19749.
  16. Plachta DT et al. Effect of cardiac-cycle-synchronized selective vagal stimulation on heart rate and blood pressure in rats. Adv Ther. 2016 Jul;33(7):1246–1261.
  17. Jiang Y et al. PPARγ upregulation induced by vagus nerve stimulation exerts anti-inflammatory effect in cerebral ischemia/reperfusion rats. Med Sci Monit. 2015 Jan 21;21:268–275.
  18. Ay I et al. Vagus nerve stimulation reduces infarct size in rat focal cerebral ischemia. Neurosci Lett. 2009 Aug 14;459(3):147–151.
  19. Chapleau MW et al. Chronic vagal nerve stimulation prevents high-salt diet-induced endothelial dysfunction and aortic stiffening in stroke-prone spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol. 2016 Jul 1;311(1):H276–H285.
  20. Olofsson PS et al. Rethinking inflammation: neural circuits in the regulation of immunity. Immunol Rev. 2012 Jul;248(1):188–204.
  21. Roemheld syndrome information and resources [Web page]. http://roemheld-syndrome.com. Accessed August 3, 2016.
  22. Puledda F, Goadsby PJ. Current approaches to neuromodulation in primary headaches: focus on vagal nerve and sphenopalatine ganglion stimulation. Curr Pain Headache Rep. 2016 Jul;20(7):47.
  23. Antherieu P et al. Vagoglossopharyngeal neuralgia revealed through predominant digestive vagal manifestations. Case report and literature review. Neurochirurgie. 2016 Jun;62(3):174–177.
  24. Holle-Lee D, Gaul C. Noninvasive vagus nerve stimulation in the management of cluster headache: clinical evidence and practical experience. Ther Adv Neurol Disord. 2016 May;9(3):230–234.
  25. Atkinson SJ. A wandering path toward prevention for acute kidney injury. J Clin Invest. 2016 May 2;126(5):1640–1642.
  26. Hornby PJ, Abrahams TP. Central control of lower esophageal sphincter relaxation. Am J Med. 2000 Mar 6;108 Suppl 4a:90S–98S.
  27. Sang Q, Goyal RK. Lower esophageal sphincter relaxation and activation of medullary neurons by subdiaphragmatic vagal stimulation in the mouse. Gastroenterology. 2000 Dec;119(6):1600–1609.
  28. Simera M et al. Changes in vagal afferent drive alter tracheobronchial coughing in anesthetized cats. Respir Physiol Neurobiol. 2016 Aug;230:36–43.
  29. Bonaz B et al. Vagus nerve stimulation: from epilepsy to the cholinergic anti-inflammatory pathway. Neurogastroenterol Motil. 2013 Mar;25(3):208–221.
  30. Lim HD et al. Anti-inflammatory effects of acupuncture stimulation via the vagus nerve. PLoS One. 2016 Mar 18;11(3):e0151882.
  31. Lu WA, Kuo CD. The effect of Tai Chi Chuan on the autonomic nervous modulation in older persons. Med Sci Sports Exerc. 2003 Dec;35(12):1972–1976.
  32. Väänänen J et al. Taichiquan acutely increases heart rate variability. Clin Physiol Funct Imaging. 2002 Jan;22(1):2–3.
  33. Wong A et al. Chronic l-citrulline supplementation improves cardiac sympathovagal balance in obese postmenopausal women: A preliminary report. Auton Neurosci. Epub 2016 Jun 24.
  34. Bond V et al. Effects of nitrate supplementation on cardiovascular and autonomic reactivity in African-American Females. ISRN Physiol. 2014 Feb 23;2014. pii:676235.
  35. Pomportes L et al. Heart rate variability and cognitive function following a multi-vitamin and mineral supplementation with added guarana (Paullinia cupana). Nutrients. 2014 Dec 31;7(1):196–208.
  36. Valera B et al. Influence of polyunsaturated fatty acids on blood pressure, resting heart rate and heart rate variability among French Polynesians. J Am Coll Nutr. 2014;33(4):288–296.
  37. Hall WL et al. Effect of low doses of long chain n-3 polyunsaturated fatty acids on sleep-time heart rate variability: a randomized, controlled trial. Int J Cardiol. 2013 Oct;168(4):4439–4442.
  38. Xin W et al. Short-term effects of fish-oil supplementation on heart rate variability in humans: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2013 May;97(5):926–935.
Posted by DrMeletis in Articles, Townsend
Mitochondria: Overlooking These Small Organelles Can Have Huge Clinical Consequences in Treating Virtually Every Disease

Mitochondria: Overlooking These Small Organelles Can Have Huge Clinical Consequences in Treating Virtually Every Disease

by Chris D. Meletis, ND, and Kimberly Wilkes

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

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

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

Conclusion

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.

Download Article:  Mitochondria: Overlooking These Small Organelles Can Have Huge Clinical Consequences in Treating Virtually Every Disease

Notes

  1. Chen Q et al. Production of reactive oxygen species by mitochondria. Central role of Complex III. J Biol Chem. September 19, 2003;278:36027–36031.
  2. Americans eat their weight in genetically engineered food [online press release]. Environmental Working Group. http://www.ewg.org/release/americans-eat-their-weight-genetically-engineered-food. Accessed October 30, 2014.
  3. Majewski MS et al. Pesticides in Mississippi air and rain: a comparison between 1995 and 2007. Environ Toxicol Chem. 2014 Jun;33(6):1283–1293.
  4. Mesnage R et al. Ethoxylated adjuvants of glyphosate-based herbicides are active principles of human cell toxicity. Toxicology. 2013;313(2–3):122–128.
  5. Mesnage R et al. Major pesticides are more toxic to human cells than their declared active principles. Biomed Res Int. 2014. Article ID 179691. Available at http://dx.doi.org/10.1155/2014/179691.
  6. Peixoto F. Comparative effects of the Roundup and glyphosate on mitochondrial oxidative phosphorylation. Chemosphere. 2005 Dec;61(8):1115–1122.
  7. Koller VJ et al. Cytotoxic and DNA-damaging properties of glyphosate and Roundup in human-derived buccal epithelial cells. Arch Toxicol. 2012 May;86(5):805–813.
  8. Madrigal JL et al. Glutathione depletion, lipid peroxidation and mitochondrial dysfunction are induced by chronic stress in rat brain. Neuropsychopharmacology. 2001 Apr;24(4):420–429.
  9. Beal MF. Mitochondria, free radicals, and neurodegeneration. Curr Opin Neurobiol. 1996 Oct;6(5):661–666.
  10. Morava E, Kozicz T. Mitochondria and the economy of stress (mal)adaptation. Neurosci Biobehav Rev. 2013 May;37(4):668–680.
  11. Mortensen OH et al. Developmental programming by high fructose decreases phosphorylation efficiency in aging offspring brain mitochondria, correlating with enhanced UCP5 expression. J Cereb Blood Flow Metab. 2014 Jul;34(7):1205–1211.
  12. Lustig RH. Fructose: it’s “alcohol without the buzz.” Adv Nutr. 2013 Mar 1;4(2):226–235.
  13. Neustadt J, Pieczenik SR. Medication-induced mitochondrial damage and disease. Mol Nutr Food Res. 2008;52:780–788.
  14. Grossniklaus U et al. Transgenerational epigenetic inheritance: how important is it? Nat Rev Genet. 2013;14:228–235.
  15. Adam M et al. Epigenetic inheritance based evolution of antibiotic resistance in bacteria. BMC Evol Biol. 2008;8:52
  16. Feinberg AP. Phenotypic plasticity and the epigenetics of human disease. Nature. 2007;447:433–440.
  17. Rogina B, Helfand SL. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci U S A. 2004;101(45):15998–16003.
  18. Wood JG et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004;430(7000):686–689.
  19. Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature. 2000;408(6809):255–262.
  20. Guarente L. Mitochondria – a nexus for aging, calorie restriction, and sirtuins? Cell. 2008;132(2):171–176.
  21. Lombard DB et al. SIRT6 in DNA repair, metabolism and ageing. J Intern Med. 2008;263(2):128–141.
  22. Kim HS et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell. 2010;17(1):41–52.
  23. Qiu X et al. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 2010;12(6):662–667.
  24. Tao R et al. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol Cell. 2010;40(6):893–904.
  25. Someya S et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell. 2010;143(5):802–812.
  26. Zhu Y et al. SIRT3 and SIRT4 are mitochondrial tumor suppressor proteins that connect mitochondrial metabolism and carcinogenesis. Cancer Metab. 2014 Oct 20;2:15. doi:10.1186/2049-3002-2-15. eCollection 2014.
  27. Singh KK. Mitochondrial dysfunction is a common phenotype in aging and cancer. Ann N Y Acad Sci. 2004;1019:260–264.
  28. Afanas’Ev IB. Mechanism of superoxide-mediated damage relevance to mitochondrial aging. Ann N Y Acad Sci. 2004;1019:343–345.
  29. Berneburg M et al. Repair of mitochondrial DNA in aging and carcinogenesis. Photochem Photobiol Sci. 2006;5(2):190–198.
  30. Singh KK. Mitochondria damage checkpoint, aging, and cancer. Ann N Y Acad Sci. 2006;1067:182–190.
  31. Dai D-F et al. Mitochondria and cardiovascular aging. Circ Res. 2012;110:1109–1124.
  32. Ershler WB, Longo DL. Aging and cancer: issues of basic and clinical science. J Natl Cancer Inst. 1997;89(20):1489–1497.
  33. Ershler WB, Longo DL. The biology of aging: the current research agenda. Cancer. 1997;80(7):1284–1293.
  34. Ahn BH et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci U S A. 2008;105(38):14447–14452.
  35. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;11(3):298–300.
  36. Rossignol DA, Frye RE. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry. 2012;17:290–314.
  37. Rose S et al. Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines. Transl Psychiatry. April 1, 2014;4(4):e377.
  38. Samavati L et al. Tumor necrosis factor alpha inhibits oxidative phosphorylation through tyrosine phosphorylation at subunit I of cytochrome c oxidase. J Biol Chem. 2008;283:21134–21344.
  39. Vempati UD et al. Role of cytochrome C in apoptosis: increased sensitivity to tumor necrosis factor alpha is associated with respiratory defects but not with lack of cytochrome C release. Mol Cell Biol. 2007;27:1771–1783.
  40. Suematsu N et al. Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation. 2003;107:1418–1423.
  41. Anitha A et al. Downregulation of the expression of mitochondrial electron transport complex genes in autism brains. Brain Pathol. 2013;23(3):294–302.
  42. Napoli E et al. Evidence of reactive oxygen species-mediated damage to mitochondrial DNA in children with typical autism. Mol Autism. 2013;4(1):2.
  43. Ross-Inta C et al. Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome. Biochem J. 2010;429(3):545–552.
  44. Andreazza AC et al. Specific subcellular changes in oxidative stress in prefrontal cortex from patients with bipolar disorder. J Neurochem. 2013;127(4):552–561.
  45. Ben-Shachar D, Karry R. Neuroanatomical pattern of mitochondrial complex I pathology varies between schizophrenia, bipolar disorder and major depression. PLoS ONE. 2008;3(11)e3676.
  46. Gubert C et al. Mitochondrial activity and oxidative stress markers in peripheral blood mononuclear cells of patients with bipolar disorder, schizophrenia, and healthy subjects. J Psychiatric Res. 2013;47(10):1396–1402.
  47. Orhan N et al. Genetic variants in nuclear-encoded mitochondrial proteins are associated with oxidative stress in obsessive compulsive disorders. J Psychiatric Res. 2012;46(2):212–218.
  48. Di Lisa F et al. Mitochondria and vascular pathology. Pharmacol Rep. 2009;61(1):123–130.
  49. Perrotta I et al. MnSOD expression in human atherosclerotic plaques: an immunohistochemical and ultrastructural study. Cardiovasc Pathol. 2013;22(6):428–437.
  50. Sobenin IA et al. Changes of mitochondria in atherosclerosis: possible determinant in the pathogenesis of the disease. Atherosclerosis. 2013;227(2):283–238.
  51. Guzik B et al. Mechanisms of oxidative stress in human aortic aneurysms – association with clinical risk factors for atherosclerosis and disease severity. Int J Cardiol. 2013;168(3):2389–2396.
  52. Hansel B et al. Metabolic syndrome is associated with elevated oxidative stress and dysfunctional dense high-density lipoprotein particles displaying impaired antioxidative activity. J Clin Endocrinol Metab. 2004;89(10):4963–4971.
  53. Palmieri VO et al. Systemic oxidative alterations are associated with visceral adiposity and liver steatosis in patients with metabolic syndrome. J Nutr. 2006;136(12):3022–3026.
  54. Koene S et al. Natural disease course and genotype-phenotype correlations in Complex I deficiency caused by nuclear gene defects: what we learned from 130 cases. J Inherit Metab Dis. 2012;35(5):737–747.
  55. Huang C et al. Depleted leukocyte mitochondrial DNA copy number in metabolic syndrome. J Atheroscler Thromb. 2011;18(10):867–873.
  56. Mitchell T, Darley-Usmar V. Metabolic syndrome and mitochondrial dysfunction: insights from preclinical studies with a mitochondrially targeted antioxidant. Free Radic Biol Med. 2012;52(5):838–840.
  57. Picard M et al. Mitochondrial allostatic load puts the ‘gluc’ back in glucocorticoids. Nat Rev Endocrinol. 2014 May;10(5):303–310.
  58. Amer MA et al. Influence of glutathione S-transferase polymorphisms on type-2 diabetes mellitus risk. Genet Mol Res. 2011;10(4):3722–3730.
  59. Khan S et al. Role and clinical significance of lymphocyte mitochondrial dysfunction in type 2 diabetes mellitus. Transl Res. 2011;158(6):344–359.
  60. Avila C et al. Platelet mitochondrial dysfunction is evident in type 2 diabetes in association with modifications of mitochondrial anti-oxidant stress proteins. Exp Clin Endocrinol Diabetes. 2012;120(4):248–251.
  61. Calabrese V et al. Oxidative stress, glutathione status, sirtuin and cellular stress response in type 2 diabetes. Biochim Biophys Acta BBA. 2012;1822(5):729–736.
  62. Gray SP et al. NADPH oxidase 1 plays a key role in diabetes mellitus-accelerated atherosclerosis. Circulation. 2013;127(18):1888–1902.
Posted by DrMeletis in Articles, Mitochondrial Health, Townsend

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