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Illnesses with mitochondrial dysfunction, including the case for ME/CFS

The first appearance of  a mitochondrial disease in the medical literature was probably the description of adult onset blindness by Theodur Lebur in 1871. 15 (This is now known as Leber's Hereditary Optic Neuroretinopathy (LHON).) 16 However, the existence of mitochondria in cells was still in the process of discovery and their role in the illness was not known. The existence of mitochondria in cells was discovered over time from 1857-1886. 17 The elucidation of their function and the role of ATP in cellular energy generation took most of the 20th century (1912-1997). 17 In 1962, Luft’s disease (which involves hypermetabolism and elevated core temperature) was the first proposed mitchondrial disease. 18 It wasn’t until 1989 that the mitochondrial and genetic bases of LHON and Luft’s illness were confirmed. 18 The first discovery of  pathogenic mitochondrial mutations in DNA was in 1988. 15 The role of inherited genetic mitochondrial defects in mitochondrial myopathies was only elucidated in the late 1980s and 1990s. 17 The role of inherited genetic mutations in fatty acid beta-oxidation enzymes started to be elucidated in the 1970s and 1980s. Many aspects are still unknown. 10

While many inherited genetic mitochondrial disorders occur in the mitochondria of all cells in the body, some are limited to specific cell sites, such as the eye, motor neurons (as in Lou Gerhig’s disease or amotrophic lateral sclerosis), skeletal muscle, or brain (as in Huntington’s disease). 10, 11, 12, 13, 14, 15, 19, 20

The role of acquired mitochondrial dysfunction in common diseases has only begun to be elucidated the last fifteen years or so. It is now known that dysfunctional mitochondria play an important role in diseases of the brain such as Alzheimer’s, and Parkinson’s. 19, 20, 21 Type-2 diabetes mellitus is also known to be an acquired mitochondrial dysfunction disease of the mitochondria in skeletal muscle and the pancreas. 3, 6, 22, 23, 24, 25, 26, 27, 28, 29

ME/CFS patients are not immune to the type-2 diabetes epidemic. So, we will note that in addition to any mitochondrial problems stemming from ME/CFS, patients also having metabolic syndrome or type-2 diabetes are having trouble with the mitochondrial problems from these conditions as well. Fewer and smaller-sized mitochondria are found in the skeletal muscle of metabolic syndrome or type-2 diabetic patients. 28 This is significant because normally 67% of the volume of skeletal muscle cells is occupied by mitochondria, compared to 20-30% of cardiac muscle cells. 28 There is diminished electron transport activity in mitochondria of skeletal muscle of diabetics that can’t be explained just by the diminished numbers of mitochondria. 3, 28 Fatty acids tend to accumulate in the cells of skeletal muscle in type-2 diabetes and this leads to reduced mitochondrial oxidative capacity. 3, 28 There is clearly a defect in the ability of skeletal muscle to oxidize fatty acids. 27 It is also the case that evidence exists of decreased mRNA (messenger RNA) expression of several genes associated with oxidative phosphorylation in first degree relatives of type-2 diabetics. 27 For a more detailed overview of the role of mitochondrial dysfunction in type-2 diabetes, see reference #27.

Since a number of ME/CFS patients are known to be also hypothyroid, hyperthyroid or have polycystic ovary syndrome (PCOS), it should be noted that insulin resistance and mitochondrial dysfunction in skeletal muscle play roles in these conditions. 29 In the cases of both hypothyroidism and hyperthyroidism, there are decreased glycogen synthesis, down-regulated intracellular glucose catabolism, altered blood flow, and decreased muscle oxidative capacity in skeletal muscle. 29 In PCOS, it is the case that there is decreased glycogen synthesis and impaired mitochondrial oxidative metabolism in skeletal muscle. 29 Thus ME/CFS patients with one or more of these additional conditions will have increased mitochondrial dysfunction in skeletal muscle, compared to ME/CFS patients who just experience post-exertional malaise.

The evidence that ME/CFS is at least in part an acquired mitochondrial dysfunction disease of skeletal muscle is now quite strong. 30, 31. 32, 33, 34, 36, 37, 38, 39, 41, 42, 43, 44, 45 We could find only one study that looked at mitochondrial function in other types of cells in CFS/ME. 40

Vermeulen et al. 30 found that in two exercise tests 24 hours apart, ME/CFS patients reached an anaerobic threshold and maximal exercise capacity at a much lower oxygen consumption than controls. This discrepancy was worse on the second test. The researchers concluded that this demonstrated an increase in lactate production and decrease in ATP production compared to controls. They did other tests that seemed to indicate that the oxidative phosphorylation occurring in both ME/CFS patients and controls was the same. So, they concluded that the dysfunction involved another pathway other than oxidative phosphorylation. (Other studies don’t agree with this conclusion.)

Kennedy et al. 31 found increased markers of oxidative stress in ME/CFS patients and that the magnitude of the increase was correlated to the symptoms of post-exertional malaise. Paul et al32 found that both ME/CFS patients and controls showed a decrease in voluntary muscle contractions during exercise consistent with fatigue following maximum voluntary contractions. Thus the researchers concluded that even though the force of the contractions were always less in the ME/CFS group, the patients were working to their maximum capacity. ME/CFS patients were unable to recover their pre-exercise force of contraction after a 200-minute recovery period that worked for healthy sedentary controls. In addition, muscle contraction force was even less 24 hours after the exercise than immediately after the exercise for the ME/CFS group. The researchers concluded that this was consistent with mitochondrial dysfunction.

In 1984, several years before CFS was defined in the U.S, Arnold et al33 found that using 31P nuclear magnetic resonance they could demonstrate an abnormal rise in intracellular acidity in the exercised forearm of a British patient with post-viral fatigue syndrome (ME). Because the rise was out of proportion to associated changes in high-energy phosphates, they concluded it demonstrated an excessive lactic acid formation due to an acquired disorder of metabolic regulation. In 1991 the Behans reported finding mitochondrial abnormalities in the biopsies of skeletal muscle of 50 ME patients. 34 (It should be noted that the patients studied by the Behans had ME after infections of skeletal muscle with enteroviruses such as Coxsackie.) Other studies have not found structural abnormalities in mitochondria. 35

In two studies, the Plioplys found that there were no obvious structural changes to mitochondria in skeletal muscle biopsies of ME/CFS patients 35, but the ME/CFS patients had statistically significant lower levels of serum total carnitine, free carnitine and acylcarnitine compared to healthy controls. 36 They concluded this was due to dysfunctional mitochondria. They also found a statistically significant correlation between lower serum total and free carnitine levels and worse clinical symptomatology. 36 Earlier, Kuratsune et al37 had discovered that deficiencies of serum acylcarnitine had statistically significantly correlated with worsened fatigue symptoms in CFS/ME patients, but the researchers had not measured total and free carnitine levels.

Using ME/CFS patients identified by the 1994 CFS case definition (which is broader than the 1988 or Canadian definitions of CFS), Lane et al38 identified two subgroups of CFS patients. One group had an abnormal rise in lactate following exercise (which they called the SATET+ve group) and the other did not (SATET-ve). They did phosphorus magnetic resonance on the forearm muscles of 10 ME/CFS SATET+ve patients, 9 ME/CFS SATET-ve patients, and 13 healthy controls. There were no differences in spectra at rest for the three groups, but after exercise the ME/CFS SATET+ve patients showed a significant increase in intracellular acidity compared to the other two groups. The ME/CFS SATET+ve patients also showed a significantly lower ATP synthesis rate during recovery from exercise than the other two groups. The researchers concluded these ME/CFS patients showed impaired oxidative phosphorylation, but the others (SATET-ve) did not.

In the book Mitochondria in Pathogenesis, Chazotte 39 gives a detailed overview of the evidence for mitochondrial dysfunction in ME/CFS as of 2000. He observed:

“Thus there is ample clinical evidence to suggest a role for mitochondrial dysfunction in many different tissues and cells in CFS, which could give rise to many of the symptoms. Whether this role is due to a specific mitochondrial defect, perhaps in genetically susceptible individuals, or is an effect of some other problem such as altered cytokine levels that in turn affect mitochondrial function, needs investigation. Due to the difficulty in obtaining human specimens in sufficient quantities per specimen for biochemically based studies of mitochondrial function, there are few (and no detailed) studies of mitochondrial function in CFS patients.” 39

Myhill et al. 40 undertook to rectify this lack of biochemically based studies and examined blood neutrophils (a type of white blood cell) of 71 ME/CFS patients and 53 healthy controls to obtain five numeric measurements of mitochondrial function, called the ATP profile test. The ME/CFS patients were ranked on the Bell CFS Ability Test (developed by Dr. David Bell) to give a scale measurement of ME/CFS severity from 0 to 10 (with 0 being “constantly bedridden with severe symptoms and unable to care for himself/herself”). The ME/CFS patients were in the “very severe” (25 patients), “severe” (21 patients) and “moderate” (25 patients) ranges on the Bell scale.

In some of the five measurements, there were ME/CFS patients who had above the minimum (but below the average) measured in the controls. The three of the most severely ill patients had one value each within the low normal range for controls, but the other four values were well below the minima for the controls. When the number of the five measurements that were below the minima of the healthy controls was taken into account by the researchers, on average the “very severe” patients had 3.7 measurements totally below the normal ranges, “severe” patients had on average 3.5, and the “moderate” patients had on average 2.2 of the five measurements below the normal ranges.

The researchers pointed out that if they had only measured one factor instead of five, significant numbers of the patients would have been classified as “normal” (albeit usually very low normal) for the factor. They stated, “For example, if only ATP had been measured, 28% of all the patients would be classified as normal, and if only Ox Phos had been measured, 32% of the ‘very severe’ patients would be classified as normal.” 40

Finally, the researchers concocted a Mitochondrial Energy Score for each patient using the five factors, which they said measured the overall mitochondrial energy-producing efficiency of the neutrophils of the study participants. Only one of the 71 patients had a Mitochondrial Energy Score above the minimum for the healthy controls. That patient had a Bell CFS Ability Score of 7, but also had two of the five factors below the minima for the healthy controls. Since the CFS Severity Score had been computed first for the patients, the researchers looked at predicting CFS severity from the Mitochondrial Energy Score.

They concluded that mitochondrial dysfunction is a major risk factor for severity in ME/CFS. However, they also noted that since they measured the ATP factors only in neutrophils, conclusions could only be reached concerning adverse effects on the function of the immune system, not in skeletal muscle. The researchers observed:

“Our observations strongly implicate mitochondrial dysfunction as the immediate cause of CFS symptoms. However, we cannot tell whether the damage to mitochondrial function is a primary effect, or a secondary effect to one or more of a number of primary conditions, for example cellular hypoxia or oxidative stress including excessive peroxynitrite." 40