Research | Mitochondrial dysfunction and the pathophysiology of ME/CFS | 30 June 2012

International Journal of Clinical and Experimental Medicine 2012;5(3):208-220
Full text available HERE.

Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome/ (ME/CFS)

Norman E Booth(1), Sarah Myhill(2), John McLaren-Howard(3)
(1) Department of Physics and Mansfield College, University of Oxford,Oxford UK;
(2) Sarah Myhill Ltd, Llangunllo, Powys UK;
(3) Acumen, Tiverton, Devon UK


The objectives of this study are to test the hypothesis that the fatigue and accompanying symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome are in part due to defects in energy provision at the cellular level, and to understand the pathophysiology of the defects so that effective medical intervention can be implemented.

We performed an audit of 138 patients (ages 18-65) diagnosed with ME/CFS and attending a private practice. The patients and 53 normal, healthy controls had the ATP Profile test carried out on neutrophils from a 3-ml venous blood sample.

This test yields 6 numerical factors that describe the availability of ATP and the efficiency of oxidative phosphorylation in mitochondria. Other biomedical measurements, including the concentration of cell-free DNA in plasma, were made.

The results of the audit are compared with the controls and a previous cohort of 61 patients.

We find that all patients tested have measureable mitochondrial dysfunction which correlates with the severity of the illness. The patients divide into two main groups differentiated by how cellular metabolism attempts to compensate for the dysfunction.

Comparisons with exercise studies suggest that the dysfunction in neutrophils also occurs in other cells. This is confirmed by the cell-free DNA measurements which indicate levels of tissue damage up to 3.5 times the normal reference range.

The major immediate causes of the dysfunction are lack of essential substrates and partial blocking of the translocator protein sites in mitochondria.

The ATP Profile is a valuable diagnostic tool for the clinical management of ME/CFS.

5 thoughts on “Research | Mitochondrial dysfunction and the pathophysiology of ME/CFS | 30 June 2012”

  1. Very pleased to see this type of research. And it would be good to see it replicated elsewhere.
    Would also be helpful to see a comparison study of whether there is similiar mitochondrial dysfunction in patients with other long term neurological conditions – M.S. or Parkinsons for eg – before concluding that the dysfunction is specific to M.E.

  2. 2 July 2012

    In a note published this morning by Co-Cure, the international M.E. and FM reading list, co-author of this paper Norman Booth writes (with respect to a contribution by Jan van Roijen):

    As ever, you are nearly always first at publicising new results. However, in this case I would like you to issue a correction.

    The problem is that IJCEM put my manuscript on their website BEFORE sending me the proof, and in the interim between submission, review and publication we authors made some extensive changes and corrections (including changing the title).

    Today IJCEM have corrected this situation, so please see their website for the final version.

    I believe that the MEA website now carries the revised abstract and a link to the corrected full text but, if this is not so, perhaps Dr Booth would care to get in touch.

  3. Neutrophils do not rely on mitochondria for ATP (energy). They use glucose. Inactivity can reduce glucose levels.

    “in human blood neutrophils the mitochondria are different, because they preserve mainly death-mediating abilities. Neutrophil mitochondria hardly participate in ATP synthesis, and have a very low activity of the tested marker enzymes.”

    We need to studies using tests that are already validated for mitochondria dysfunction.

  4. In a comment posted on 30 June 2012 JoT states: “Neutrophils do not rely on mitochondria for ATP (energy).” The link given to substantiate this statement is to a paper published in 2004 by Maianski et al. That work concentrates almost entirely on the aspects of neutrophils with regard to apoptosis (programmed cell death). That work is also referenced in a 2010 paper by Vermeulen et al. and we have already published a Comment on this paper in which we also discuss our apparent disagreement with some of the results of Maianski et al
    You can be certain that (because of evolution) neutrophils use the most appropriate energy transformation processes in order to carry out their roles in cellular physiology. Their main role is to find infiltrating invaders (viruses, foreign bacteria and other foreign bodies), kill them, and dispose of them. They patrol, searching for invaders, using sensors (chemotaxis). My co-author, John McLaren Howard (JMH) using the sophisticated technique of fluorescence microscopy, has observed ATP molecules travelling from mitochondria along actin filaments to the cell membrane where they provide energy for the vigorous motility of neutrophils. Figure 3A of our paper clearly shows that on average 93% of their ATP is produced by mitochondria. When a neutrophil discovers a chemical gradient due to an invader its motility increases as it homes in for the kill. It is only at this stage that anaerobic metabolism could start to become important. During the kill and phagocytosis its ATP supply might be nearly all anaerobic, but oxygen is also used at this stage (respiratory burst) to produce highly reactive superoxides to complete the kill.
    We have checked that adding sodium azide to an aerated suspension of neutrophil mitochondria completely stops oxygen uptake within 3 minutes, whether or not ADP is added before the sodium azide. We have also repeated the process of adding sodium azide to neutrophils suspended in an aerated buffer solution and found that aerobic metabolism is completely stopped within 3 minutes. We always at this point wash away the inhibitor and the ATP concentration increases. Maianski et al. measured the ATP 6 hours after adding the inhibitor and we do not know if any of their neutrophils died during this period or what, if any, compensatory process produced more ATP. Apoptosis is the final event in the lifetime of neutrophils, and is not representative of their main activities.

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