New award from the MEA Ramsay Research Fund for further mitochondrial research | 21 July 2015

July 21, 2015


ME ASSOCIATION RAMSAY RESEARCH FUND:RESEARCH FUNDING ANNOUNCEMENT

Comparison of results from a commercial and a clinical diagnostic-based blood test to assess mitochondrial function in ME/CFS

The MEA Ramsay Research Fund is pleased to announce an award of £21,305 to Dr Sarah Jayne Boulton and colleagues at Newcastle University.

The award will be funding a new research study that will be comparing the results of a commercial blood test for mitochondrial function that has been developed by Dr Sarah Myhill and colleagues with the results from an international and widely accepted test of mitochondrial function which has a long and successful track record in clinical diagnosis and research of muscle disease, particularly in the UK.

BACKGROUND

Mitochondria play a vital role in energy production at a cellular level, especially in skeletal muscle, and a number of research studies – including some carried out at Newcastle University – have demonstrated abnormalities in muscle in people with ME/CFS that are linked to mitochondrial function.

The ME Association therefore believes that research into mitochondrial dysfunction in ME/CFS should be a high priority research item – as does the Medical Research Council.

This is why we have already funded a study that was carried out by Professor Julia Newton and colleagues at Newcastle University and we are currently funding, along with the Medical Research Council, further research into mitochondrial dysfunction. This is being carried out by Professor Anne McArdle and colleagues at the University of Liverpool.

We have also made a contribution to research that is being carried out by Dr Joanna Elson at Newcastle University, which is looking at mitochondrial DNA.

DIAGNOSIS OF MITOCHONDRIAL DYSFUNCTION

Interest in the role of mitochondrial dysfunction in ME/CFS has also led to the development of a commercial blood test – often referred to as the ATP profiling test – by Dr Sarah Myhill and colleagues (references 1 and 2).

In very simple terms, the test measures a number of components that determine a person's ability to generate a substance called ATP, which is the cell's unit of energy currency at a molecular level.

However, this test has not been validated by independent assessments. It is not therefore used to diagnose mitochondrial disease in the NHS.

The comparison study involves using a series of spectroscopic assays which are based upon published assays both for research and diagnosing mitochondrial disease, and the functionality of individual mitochondrial respiratory complexes are determined. These assays have been validated by other independent groups and laboratories.

These respiratory chain complexes, like links in a chain, must all be fully functional and tightly cooperative to allow the necessary ATP-producing oxidative phosphorylation reactions to occur. Any ‘weak link' in the respiratory chain will result in sub-optimal respiratory function, poor ATP production and metabolic dysfunction, of which fatigue is a major symptom.

An array of spectroscopic mitochondrial diagnostic techniques to measure the respiratory chain complexes were first reported by Newcastle University in 1994 (reference 3) and were the foundation for current clinical diagnostic assays in the UK.

And in October 2014, Dr Boulton began a six month project funded by the MRC Confidence in Concept call that investigates the usefulness of the spectroscopic methods in stratifying ME/CFS patients based on their mitochondrial respiratory complex function.

Pilot data that supported the hypothesis of mitochondrial respiratory Complex II involvement in fatigue was generated from cultured muscle.

HOW WILL THIS COMPARISON OF TESTS WILL BE CARRIED OUT?

The research will involve a comparison between the data generated using the ATP profiling tests and the established mitochondrial complex assays using spectrophotometric techniques.

The aim is to determine the efficacy of each set of tests in relation to ME/CFS. In the exciting case that a synergy between the two diagnostic approaches exists, it is hoped that this preliminary study will promote an investigation into a more inclusive and highly resolved analytical technique for metabolic testing of people with ME/CFS.

REFERENCES

1. Myhill, S., Booth, N. E., and McLaren-Howard, J. (2009) Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med 2, 1-16

2. Booth, N. E., Myhill, S., and McLaren-Howard, J. (2012) Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Int J Clin Exp Med 5, 208-220

3. Birch-Machin, M. A., Briggs, H. L., Saborido, A. A., Bindoff, L. A., and Turnbull, D. M. (1994) An evaluation of the measurement of the activities of complexes I-IV in the respiratory chain of human skeletal muscle mitochondria.
Biochem Med Metab Biol 51, 35-42

2 thoughts on “New award from the MEA Ramsay Research Fund for further mitochondrial research | 21 July 2015”

  1. This sounds very exciting and good news that it has the backing and funding to carry it forward.

    Thank you Ramsay Research, MEA and all involved. Newcastle are certainly leading the way in many diseases. It’s good to know the North East has great things to offer.

    Thank you

  2. I am very pleased that finally, another group has decided and been funded to check the Acumen measurements of ATP concentrations in human cells and other aspects of the function or dysfunction of their mitochondria. It is very important to assay mitochondrial dysfunction in a way that is straightforward and which yields the most physiologically relevant, unambiguous and informative results.

    In our first paper [1] we showed that 70% of ME/CFS patients had below normal levels of ATP in their neutrophils and all had some degree of mitochondrial dysfunction. In our second paper [2] we found (actually to our own amazement) that for about ½ of both treated and untreated patients, a substantial fraction of their ATP was being produced, not by the electron transfer chain or anaerobic glycolysis, but by another process. We have since then determined that this other process is also anaerobic (no oxygen uptake). In the early days of Dr Sarah Myhill using tests carried out by Dr John McLaren-Howard the functionality of certain enzymes (or complexes) in the mitochondrial electron transfer chain were measured. It was found that the results did not correlate with clinical ability, and over several years the present ATP Profile and other tests were developed. In a recent review of the techniques for assessing mitochondrial function in cells, Brand and Nicholls (reference [11] of our second paper) concluded that the amount of cellular ATP does not necessarily report mitochondrial function because there can be pathways which try to compensate for any dysfunction [3]. In fact, the most likely compensatory pathway (the adenine nucleotide pathway) not only explains the effects that we reported, but also predicts post-exertional malaise, the prime symptom of ME/CFS, on the timescale of a few days [4].

    Brand and Nicholls also point out that measuring the functionality of individual mitochondrial respiratory complexes, as planned by Dr Boulton, is not very useful because no single complex is rate limiting [3]. Also, function depends upon the integrity of many processes. The chain as a whole has to function, but it is more like an assembly line – and don’t forget the doors that let the essential parts and co-factors come in, or the door that lets out the final product, ATP.

    Many medical doctors use the Acumen ATP Profile and auxiliary tests. It is important that as a first step a second party replicates some of these so that results from the same blood samples can be compared. Where necessary improved techniques can be implemented.

    The Acumen measurements take place in vitro but they study blood cells that are still alive. Some of the tests are on mitochondria isolated from the cells, but the mitochondria are still functional.

    Ideally, we would like to measure cells in vivo in different parts of the body, for example in skeletal muscle. This is now possible using near infrared spectrometry (NIR) and sophisticated electronics [5] but this technique has not yet been used on ME/CFS patients. It may take some time but I look forward to having an APP on my smart phone to receive and analyze the signals from NIR sensors taped onto my muscles. In the meantime I wish Dr Boulton every success in this new project.

    REFERENCES
    1. Myhill, S., N.E. Booth, and J. McLaren-Howard, Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med, 2009. 2(1): p. 1-16.
    2. Booth, N.E., S. Myhill, and J. McLaren-Howard, Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). International Journal of Clinical and Experimental Medicine, 2012. 5(3): p. 208-220.
    3. Brand, M.D. and D.G. Nicholls, Assessing mitochondrial dysfunction in cells. Biochemical Journal, 2011. 435(2): p. 297-312.
    4. Lengert, N. and B. Drossel, In silico analysis of exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Biophysical Chemistry, 2015. 202(0): p. 21-31.
    5. Binzoni, T., et al., A new method to measure local oxygen consumption in human skeletal muscle during dynamic exercise using near-infrared spectroscopy. Physiological Measurement, 2010. 31(9): p. 1257-1269.

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