Chronic Fatigue Syndrome (CFS) is a multisystem illness that robs its victims of their health and their dignity. Two of the most characteristic and debilitating signs of CFS are very poor stamina and delayed post-exertional fatigue. Sometimes the fatigue is mainly mental, and sometimes mainly physical. Fatigue is the same as lack of energy and energy comes from the basic metabolic process of the oxidation of food.
A widely-held hypothesis (A) is that the metabolism of people with CFS is normal, but the fatigue and other symptoms are due to psychological factors. It is acknowledged that physical fatigue is lack of energy, but mental fatigue is considered to be a subjective sensation characterized by lack of motivation and of alertness [1
], even though the brain is a major consumer of resting cellular energy. Patients may demonstrate negative illness beliefs that increase the severity of the symptoms [2
]. However, if the metabolism is functioning properly, the fatigue and related symptoms must be due to energy being wasted by the mental and physical processes of stress, anxiety, tension and depression. Patients should be able to be helped, possibly cured by psychological intervention, e.g. cognitive behavioural therapy. In order to explain the post-exertional malaise an ancillary hypothesis (A′) is needed, namely deconditioning due to disuse of muscles. However, hypothesis A′ is not supported by experiment in many cases as we will see below.
An alternative hypothesis (B) is that there is a metabolic dysfunction with the result that not enough energy is being produced. The main source of energy comes from the complete oxidation of glucose to carbon dioxide and water. 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 or pancreatic insufficiency, energy production will be impaired and fatigue may result [4
]. These conditions can and should be tested for. Allergies and thyroid malfunction can also produce fatigue.
When the digestive system is functioning properly glucose and lipids are fed into the blood stream where, together with oxygen bound to hemoglobin in erythrocytes (red blood cells), they are transported to every cell in the body. In the cytosol of each cell glucose is broken down in a series of chemical reactions called glycolysis into two molecules of 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 are dictated by the typical energy requirements; cardiac and skeletal muscle cells and liver and brain cells contain the highest numbers. The mitochondria generate energy by oxidative metabolism in the form of ATP (adenosine triphosphate) which when hydrolysed to the diphosphate, ADP, releases energy to produce muscle contractions, nerve impulses and all the energy-consuming processes including the chemical energy needed to synthesise all of the complex molecules of the body [5
]. Thus, mitochondrial dysfunction will result in fatigue and can produce other symptoms of CFS.
The two hypotheses are not mutually exclusive. Some patients may satisfy both. However there are constraints; the basal metabolic rate (about 7000 kJ per day) must be maintained and the first law of thermodynamics must not be violated.
There is considerable evidence that mitochondrial dysfunction is present in some CFS patients. Muscle biopsies studied by electron microscopy have shown abnormal mitochondrial degeneration [7
]. Biopsies have also found severe deletions of genes in mitochondrial DNA (mtDNA), genes that are associated with bioenergy production [9
]. One consequence of mitochondrial dysfunction is increased production of free radicals which cause oxidative damage. Such oxidative damage and increased activity of antioxidant enzymes has been detected in muscle specimens [11
]. Some essential compounds (carnitine and N-acylcarnitine) needed for some metabolic reactions in mitochondria have been measured in serum and found to be decreased in patients with CFS [12
]. Both studies found that the carnitine levels correlated with functional capacity. Reduced oxidative metabolism [14
] 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 was observed and a lower rate of ATP synthesis during recovery was measured [18
]. These findings suggest impaired recycling of ADP to ATP in the mitochondria.
However, there are also some similar studies that do not confirm mitochondrial dysfunction. This situation is likely due to the different diagnostic criteria in use. For example, the Oxford criteria [1
], a definition proposed by psychiatrists, require only fatigue; “other symptoms may be present” but are not essential. The Centers for Disease Control (CDC) criteria are more selective as they require an additional four symptoms from a list of eight [19
]. In England in 2007 the National Institute for Clinical Excellence (NICE) introduced yet another set of criteria, fatigue plus one more symptom, for example “persistent sore throat” [20
]. At the other end of the spectrum are criteria based on studies of patients with Myalgic Encephalomyelitis (ME) [21
] which have culminated in the Canadian consensus criteria [24
]; the Canadian criteria are unlikely to include patients satisfying only hypothesis A. Even more confusingly, both the Canadian and the new NICE criteria use the term ME/CFS although their criteria are very different. At the present time the CDC criteria are internationally widely used as the criteria for research purposes despite their lack of precision [25
]. This situation may change in the future because the Canadian criteria are gaining wider acceptance and one charitable research funding agency (ME Research UK) now requires both the CDC and Canadian criteria to be used in research projects that it funds. We use the term CFS or CFS/ME for the CDC criteria and ME/CFS for the Canadian criteria. Our study is aimed to assess the role of mitochondrial dysfunction with the primary aim of helping patients
Hypothesis B is attractive because mitochondrial dysfunction in various organs offers possible explanations for many of the other symptoms of CFS and ME. There is mounting evidence that the symptoms are due to dysfunctions on the cellular level. Abnormalities have been seen in immune cells [26
], and gene expression studies have revealed abnormalities in genes associated with immune cells, brain cells, skeletal muscle cells, the thyroid, and mitochondria [27
]. A further genetic study identified seven clinical phenotypes [29
]. There seem to be three distinct clusters of clinical abnormalities that define CFS [30
]: (a) blood flow and vascular abnormalities such as orthostatic intolerance (vascular system), (b) widespread pain, and high sensitivities to foods, temperature, light, noise and odours (central nervous system sensitization), and (c) fatigue, exhaustion and brain 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 dysfunction can also produce abnormalities (a) and (b) because ATP produced in each cell by its mitochondria is the major source of energy for all body functions.
These observations from biomedical research into CFS are very encouraging, but how long do patients have to wait before there is some real progress in ameliorating their symptoms? In a private medical practice which specializes in CFS the primary goal is to make the patients feel and function better. Treatment is started by making use of the existing biomedical knowledge to provide a basis of nutrition, lifestyle management and pacing. Thyroid, adrenal and allergy problems are also addressed if they occur. Most patients improve with these interventions. However, in many cases the improvement is not as great as the patient and doctor would like. When one of us (SM) became aware of the commercial “ATP profile” testing package it was thought that this might be useful in predicting the level of disability and identifying any biochemical lesions that were at fault. The “ATP profile” testing package, developed by one of us (JMH), is designed specifically for CFS and other conditions where energy availability is reduced. It was found early on that the “ATP profile” was very useful in predicting the level of disability and suggesting the most likely interventions which would benefit patients. Tests have now been carried out on a number of patients and also on normal, healthy subjects. When collated the test results show features that were completely unexpected. Before we report here on the test procedures and results we provide a brief summary of how mitochondria produce energy.
Mitochondrial energy metabolism
In each cell glucose is broken down to pyruvate with the production of some ATP (2 molecules net per molecule of glucose). The pyruvate and also fatty acids enter the mitochondria of each cell, shown schematically in , where two coordinated metabolic processes take place: the tricarboxylic acid (TCA) cycle, also known as the Krebs' citric acid cycle, which produces some ATP, and the electron transport chain (ETC, also called the Respiratory Chain because it uses most of the oxygen we breathe in) which regenerates ATP from ADP by the process of oxidative phosphorylation (ox-phos). Altogether some 30-odd molecules of ATP are produced per molecule of glucose and these constitute the main cellular energy packets used for all life processes. As well as food and oxygen the metabolic pathways require all the nutrients involved in the production of the large number of enzymes which control the many biochemical reactions involved and all the cofactors needed to activate the enzymes [31
]. Most of the enzymes are coded by nuclear DNA (nDNA) in the cell's nucleus and a few are coded by mtDNA. Some of the enzymes 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 problem can lead to fatigue and this can be tested for. The human body contains typically less than 100 g of ATP at any instant, but can consume up to 100 kg per day. Thus the recycling ox-phos process is extremely important and it produces more than 90% of our cellular energy. The main features and processes are illustrated in a simplified form in (further details can be found in all college-level textbooks on biochemistry, e.g. [6
], and in secondary school advanced-level biology textbooks, e.g. [35
]). The ETC culminates with the protein complex ATP synthase which is effectively a reversible stepping motor in which 3 ATP molecules are produced from ADP and inorganic phosphate (Pi
) every revolution [36
]. Because of evolutionary history ATP is made inside the mitochondrial inner membrane but used outside in the cytosol where it releases energy by converting to ADP and Pi
. The Pi as a negative ion is co-transported back inwards together with H+
, while ADP3−
is transported inwards through the Translocator protein adenosine nucleotide translocase (TL or ANT) in exchange for ATP4−
moving out into the cytosol. There are potential problems here because it is known that some specific molecules (e.g. atractyloside) block the transfer inwards and certain others can block transfer outwards [37
], and there is the possibility that there may be other molecules including environmental contaminants which can block transfers.
Figure 1 Main stages and location of energy metabolism in a human cell (left), and simplified details of a mitochondrion showing the main metabolic cycles and the oxidative phosphorylation respiratory chain (right). The outer mitochondrial membrane is highly permeable (more ...)
What happens if some part of these cellular metabolic pathways goes wrong? If the mitochondrial source of energy is dysfunctional many disease symptoms may appear [38
] including the symptoms of CFS.
Suppose that the demand for ATP is higher than the rate at which it can be recycled. This happens to athletes during the 100 meters sprint. The muscle cells go into anaerobic metabolism where each glucose molecule is converted into 2 molecules of lactic acid. This process is very inefficient (5.2% energy production compared to the 100% of complete oxidation) and can last for only a few minutes. The increased acidity leads to muscle pain. Also, when the concentration of ADP in the cytosol increases and the ADP cannot be recycled quickly enough to ATP, another chemical reaction takes place. This becomes important if there is any mitochondrial dysfunction. Two molecules of ADP interact to produce one of ATP and one of AMP (adenosine monophosphate). The AMP cannot be recycled [6
] and thus half of the potential ATP is lost. This takes some days to replenish and may account for the post-exertional malaise symptom experienced by patients [39
Thus, mitochondrial dysfunction resulting in impaired ATP production and recycling is a biologically plausible hypothesis, and there is considerable evidence that it is a contributory factor in CFS, at least for a subset of patients. Our study may be considered to be a test of this hypothesis.