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Chronic Fatigue Syndrome and Mitochondrial Dysfunction

Chronic Fatigue Syndrome and Mitochondrial Dysfunction

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Published by karlmalatesta
The similarities between CFS and the microwave syndrome are amazing. A common pathway of damage seems to underlie the international epidemic of patients with CFS and microwave syndrome.
The similarities between CFS and the microwave syndrome are amazing. A common pathway of damage seems to underlie the international epidemic of patients with CFS and microwave syndrome.

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Published by: karlmalatesta on Jul 10, 2010
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Int J Clin Exp Med (2009) 2, 1-16www.ijcem.com /IJCEM812001
Original Article
Chronic fatigue syndrome and mitochondrial dysfunction
Sarah Myhill
, Norman E. Booth
, John McLaren-Howard
Sarah Myhill Limited, Llangunllo, Knighton, Powys, Wales LD7 1SL, UK 
Department of Physics and MansfieldCollege, University of Oxford, Oxford OX1 3RH, UK 
 Acumen, PO Box 129, Tiverton, Devon EX16 0AJ, UK 
Received December 2, 2008; accepted January 12, 2009; available online January 15, 2009
This study aims to improve the health of patients suffering from chronic fatigue syndrome (CFS) byinterventions based on the biochemistry of the illness, specifically the function of mitochondria in producing ATP(adenosine triphosphate), the energy currency for all body functions, and recycling ADP (adenosine diphosphate) to replenish the ATP supply as needed. Patients attending a private medical practice specializing in CFS werediagnosed using the Centers for Disease Control criteria. In consultation with each patient, an integer on the BellAbility Scale was assigned, and a blood sample was taken for the “ATP profile” test, designed for CFS and otherfatigue conditions. Each test produced 5 numerical factors which describe the availability of ATP in neutrophils, the fraction complexed with magnesium, the efficiency of oxidative phosphorylation, and the transfer efficienciesof ADP into the mitochondria and ATP into the cytosol where the energy is used. With the consent of each of 71patients and 53 normal, healthy controls the 5 factors have been collated and compared with the Bell AbilityScale. The individual numerical factors show that patients have different combinations of biochemical lesions.When the factors are combined, a remarkable correlation is observed between the degree of mitochondrialdysfunction and the severity of illness (
<0.001). Only 1 of the 71 patients overlaps the normal region. The “ATPprofile” test is a powerful diagnostic tool and can differentiate patients who have fatigue and other symptoms asa result of energy wastage by stress and psychological factors from those who have insufficient energy due tocellular respiration dysfunction. The individual factors indicate which remedial actions, in the form of dietarysupplements, drugs and detoxification, are most likely to be of benefit, and what further tests should be carriedout.
Key Words:
Chronic fatigue syndrome, myalgic encephalomyelitis, mitochondria, neutrophils, oxidativephosphorylation.
Chronic Fatigue Syndrome (CFS) is amultisystem illness that robs its victims of theirhealth and their dignity. Two of the mostcharacteristic and debilitating signs of CFS arevery poor stamina and delayed post-exertionalfatigue. Sometimes the fatigue is mainlymental, and sometimes mainly physical.Fatigue is the same as lack of energy andenergy comes from the basic metabolicprocess of the oxidation of food.A widely-held hypothesis (A) is that themetabolism of people with CFS is normal, but the fatigue and other symptoms are due topsychological factors. It is acknowledged thatphysical fatigue is lack of energy, but mentalfatigue is considered to be a subjectivesensation characterized by lack of motivationand of alertness [1], even though the brain is amajor consumer of resting cellular energy.Patients may demonstrate negative illnessbeliefs that increase the severity of thesymptoms [2, 3]. However, if the metabolism isfunctioning properly, the fatigue and relatedsymptoms must be due to energy being wasted by the mental and physical processesof stress, anxiety, tension and depression.Patients should be able to be helped, possiblycured by psychological intervention, e.g.cognitive behavioural therapy. In order toexplain the post-exertional malaise an ancillaryhypothesis (A') is needed, namelydeconditioning due to disuse of muscles.However, hypothesis A' is not supported by
Chronic fatigue syndrome and mitochondrial dysfunction
Int J Clin Exp Med (2009) 2, 1-162experiment in many cases as we will seebelow.An alternative hypothesis (B) is that there is ametabolic dysfunction with the result that notenough energy is being produced. The mainsource of energy comes from the completeoxidation of glucose to carbon dioxide andwater. The digestive system produces glucose,glycerol and fatty acids, and amino acids. If  there is a problem with the digestive system,e.g. gut fermentation, hypochlorhydria orpancreatic insufficiency, energy production willbe impaired and fatigue may result [4]. Theseconditions can and should be tested for.Allergies and thyroid malfunction can alsoproduce fatigue.When the digestive system is functioning properly glucose and lipids are fed into theblood stream where, together with oxygenbound to hemoglobin in erythrocytes (redblood cells), they are transported to every cellin the body. In the cytosol of each cell glucoseis broken down in a series of chemicalreactions called glycolysis into two moleculesof pyruvate which enter the energy-producing organelles present in most cells of the body, the mitochondria. Some structural details and the number of mitochondria per cell aredictated by the typical energy requirements;cardiac and skeletal muscle cells and liver andbrain cells contain the highest numbers. Themitochondria generate energy by oxidativemetabolism in the form of ATP (adenosine triphosphate) which when hydrolysed to thediphosphate, ADP, releases energy to producemuscle contractions, nerve impulses and all the energy-consuming processes including thechemical energy needed to synthesise all of  the complex molecules of the body [5, 6].Thus, mitochondrial dysfunction will result infatigue and can produce other symptoms of CFS.The two hypotheses are not mutuallyexclusive. Some patients may satisfy both.However there are constraints; the basalmetabolic rate (about 7000 kJ per day) mustbe maintained and the first law of  thermodynamics must not be violated.There is considerable evidence thatmitochondrial dysfunction is present in someCFS patients. Muscle biopsies studied byelectron microscopy have shown abnormalmitochondrial degeneration [7-9]. Biopsieshave also found severe deletions of genes inmitochondrial DNA (mtDNA), genes that areassociated with bioenergy production [9, 10].One consequence of mitochondrialdysfunction is increased production of freeradicals which cause oxidative damage. Suchoxidative damage and increased activity of antioxidant enzymes has been detected inmuscle specimens [11]. Some essentialcompounds (carnitine and N-acylcarnitine)needed for some metabolic reactions inmitochondria have been measured in serumand found to be decreased in patients withCFS [12, 13]. Both studies found that thecarnitine levels correlated with functionalcapacity. Reduced oxidative metabolism [14-16] and higher concentrations of xenobiotics,lactate and pyruvate [17] have been reported.In one group of patients a decrease of intracellular pH after moderate exercise wasobserved and a lower rate of ATP synthesisduring recovery was measured [18]. Thesefindings suggest impaired recycling of ADP toATP in the mitochondria.However, there are also some similar studies that do not confirm mitochondrial dysfunction.This situation is likely due to the differentdiagnostic criteria in use. For example, theOxford criteria [1], a definition proposed bypsychiatrists, require only fatigue; “othersymptoms may be present” but are notessential. The Centers for Disease Control(CDC) criteria are more selective as theyrequire an additional four symptoms from a listof eight [19]. In England in 2007 the NationalInstitute for Clinical Excellence (NICE)introduced yet another set of criteria, fatigueplus one more symptom, for example“persistent sore throat” [20]. At the other endof the spectrum are criteria based on studiesof patients with Myalgic Encephalomyelitis(ME) [21-23] which have culminated in theCanadian consensus criteria [24]; theCanadian criteria are unlikely to includepatients satisfying only hypothesis A. Evenmore confusingly, both the Canadian and thenew NICE criteria use the term ME/CFSalthough their criteria are very different. At thepresent time the CDC criteria areinternationally widely used as the criteria forresearch purposes despite their lack of precision [25]. This situation may change in the future because the Canadian criteria aregaining wider acceptance and one charitableresearch funding agency (ME Research UK)now requires both the CDC and Canadian
Chronic fatigue syndrome and mitochondrial dysfunction
Int J Clin Exp Med (2009) 2, 1-163criteria to be used in research projects that itfunds. We use the term CFS or CFS/ME for theCDC criteria and ME/CFS for the Canadiancriteria. Our study is aimed to assess the roleof mitochondrial dysfunction with the primaryaim of helping patientsHypothesis B is attractive becausemitochondrial dysfunction in various organsoffers possible explanations for many of theother symptoms of CFS and ME. There ismounting evidence that the symptoms are due to dysfunctions on the cellular level.Abnormalities have been seen in immune cells[26], and gene expression studies haverevealed abnormalities in genes associatedwith immune cells, brain cells, skeletal musclecells, the thyroid, and mitochondria [27, 28]. Afurther genetic study identified seven clinicalphenotypes [29]. There seem to be threedistinct clusters of clinical abnormalities thatdefine CFS [30]: (a) blood flow and vascularabnormalities such as orthostatic intolerance(vascular system), (b) widespread pain, andhigh sensitivities to foods, temperature, light,noise and odours (central nervous systemsensitization), and (c) fatigue, exhaustion andbrain fog (impaired energy production).Hypothesis B is that the lack of energy in the third cluster originates in the mitochondria of individual cells. But mitochondrial dysfunctioncan also produce abnormalities (a) and (b)because ATP produced in each cell by itsmitochondria is the major source of energy forall body functions.These observations from biomedical researchinto CFS are very encouraging, but how long dopatients have to wait before there is some realprogress in ameliorating their symptoms? In aprivate medical practice which specializes inCFS the primary goal is to make the patientsfeel and function better. Treatment is startedby making use of the existing biomedicalknowledge to provide a basis of nutrition,lifestyle management and pacing. Thyroid,adrenal and allergy problems are alsoaddressed if they occur. Most patients improvewith these interventions. However, in manycases the improvement is not as great as thepatient and doctor would like. When one of us(SM) became aware of the commercial “ATPprofile” testing package it was thought that this might be useful in predicting the level of disability and identifying any biochemicallesions that were at fault. The “ATP profile” testing package, developed by one of us(JMH), is designed specifically for CFS andother conditions where energy availability isreduced. It was found early on that the “ATPprofile” was very useful in predicting the levelof disability and suggesting the most likelyinterventions which would benefit patients.Tests have now been carried out on a numberof patients and also on normal, healthysubjects. When collated the test results showfeatures that were completely unexpected.Before we report here on the test proceduresand results we provide a brief summary of howmitochondria produce energy.
Mitochondrial energy metabolism
In each cell glucose is broken down topyruvate with the production of some ATP (2molecules net per molecule of glucose). Thepyruvate and also fatty acids enter themitochondria of each cell, shownschematically in
Figure 1
, where twocoordinated metabolic processes take place: the tricarboxylic acid (TCA) cycle, also knownas the Krebs’ citric acid cycle, which producessome ATP, and the electron transport chain(ETC, also called the Respiratory Chainbecause it uses most of the oxygen we breathein) which regenerates ATP from ADP by theprocess of oxidative phosphorylation (ox-phos).Altogether some 30-odd molecules of ATP areproduced per molecule of glucose and theseconstitute the main cellular energy packetsused for all life processes. As well as food andoxygen the metabolic pathways require all thenutrients involved in the production of thelarge number of enzymes which control themany biochemical reactions involved and all the cofactors needed to activate the enzymes[31-33]. Most of the enzymes are coded bynuclear DNA (nDNA) in the cell’s nucleus and afew are coded by mtDNA. Some of theenzymes rely on other organs. For example, thyroid hormone is needed in the TCA cycle. On the other hand hyperthyroidism can uncouple the ox-phos process [34], so a thyroid problemcan lead to fatigue and this can be tested for.The human body contains typically less than100 g of ATP at any instant, but can consumeup to 100 kg per day. Thus the recycling ox-phos process is extremely important and itproduces more than 90% of our cellularenergy. The main features and processes areillustrated in a simplified form in
Figure 1
 (further details can be found in all college-level textbooks on biochemistry, e.g. [6], and insecondary school advanced-level biology

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