Charlotte Stephens, Research Correspondent, ME Association.
Dr Cara Tomas completed her PhD at Newcastle University last year and has personal experience of M.E.
In 2017, she shared her thoughts with us on research that had examined mitochondrial function.
That research and Cara’s own experiences of M.E. were covered in a widely shared article from the New Scientist.
Cara has continued to study energy production and the role of mitochondria in ME/CFS and in February published a review that aimed to summarise what we have learned, from this team’s perspective:
|“Thus far, we have shown that ME/CFS patients do not harbor proven mtDNA mutations, another exclusion, albeit an important one. As such this group of patients do not fall within the category of patients with mitochondrial disorder.”
“If ME/CFS patients have some form of mitochondrial dysfunction, the form and cause of this dysfunction is a matter of debate.”
Earlier in March, the Newcastle team (Cara Tomas, Joanna Elson, Julia Newton and Audrey Brown) published a new study that examined mitochondrial activity in permeabilised cells from people with ME/CFS.
Cara has kindly agreed to again provide us with a summary explanation of this rather complex study, and this can be found below.
Abnormalities in mitochondrial function have previously been shown in chronic fatigue syndrome (CFS) patients, implying that mitochondrial dysfunction may contribute to the pathogenesis of disease.This study builds on previous work showing that mitochondrial respiratory parameters are impaired in whole cells from CFS patients by investigating the activity of individual mitochondrial respiratory chain complexes.Results showed there to be no significant differences in individual mitochondrial complex activity or respiratory activity supported by fatty acid oxidation or glutaminolysis between healthy control and CFS cohorts in either skeletal muscle or PBMCs.The lack of difference in complex activity in CFS PBMCs suggests that the previously observed mitochondrial dysfunction in whole PBMCs is due to causes upstream of the mitochondrial respiratory chain.
Abnormal energy production pathway in ME/CFS
“Our previous work showed mitochondrial respiration, the process by which ATP is generated, to be decreased in ME/CFS patients. We wanted to try and identify what part of the energy production pathway is abnormal.”
|Mitochondria are referred to as the ‘powerhouse’ of a cell. They are like energy factories that generate cellular energy in the form of a small molecule called ‘ATP’.|
“The final process of mitochondrial ATP production is carried out by the movement of sub-atomic particles called electrons though five protein complexes. The movement of electrons between the protein complexes is used to generate ATP by capturing the energy of the electrons.”
“Our work has used two cell types in order to see how the protein complexes are functioning in patients and healthy controls. We used peripheral blood mononuclear cells (PBMCs) which were used for our previous research. We also used skeletal muscle cells as post-exertional malaise and muscle pain are symptoms often experienced by patients.”
|PBMC’s are a type of white blood cell that are widely used in research as they are an easily accessible form of immune cell found throughout the bloodstream.|
“Work by other ME/CFS research groups has previously looked at mitochondrial respiratory chain activity in both cell types. The techniques we applied were different and novel in this context.”
“We used a cutting-edge technique (extracellular flux analysis with permeabilised cells) to determine the mitochondrial respiratory complex function.”
“This technique allowed us to investigate the activity of each of the mitochondrial complexes in turn by using combinations of chemicals that stimulated and inhibited each of the complexes.”
Upstream energy production abnormalities now considered most likely
“Our results showed no differences in activity of any of the mitochondrial complexes in either cell type.”
“Our experiments using PBMCs showed comparable levels of mitochondrial complex function between the patient and control cells. This is similar to what Lawson et al. showed using a different technique.”
“This implies that what we observed in our previous experiment using whole cells (lower mitochondrial respiration in ME/CFS) is caused by abnormalities in the energy production pathways upstream of the mitochondrial complexes.”
“However, caution must be used when interpreting these results as we had to permeabilise (put holes in) the cell membrane in order to conduct these experiments, which makes the results less physiologically relevant than the experiments conducted using whole cells, which is a more natural environment for the mitochondria.”
Future research directions
“While our skeletal muscle cell results fit with previous research showing no difference between ME/CFS and control complex activity, our results were very variable.”
“Ultimately, our results show that future studies wanting to pinpoint the process or processes that are different regarding ATP production by mitochondria in ME/CFS should focus on the parts of the pathways that precede the mitochondrial complexes.”
Cara’s work supports the results of other research in this area that is suggesting it may not be the mitochondria themselves that are ‘faulty’, as was previously believed, but rather something just upstream of the mitochondria that is having an effect on their function.
The ME Association is currently working on a major research summary that will explain where things stand with energy production and mitochondrial research in ME/CFS. We hope to publish before the end of the March.
- The Emerge ME/CFS research conference currently taking place in Australia includes talks about energy production and mitochondria. Cara Tomas presented her work on ‘cellular bioenergetics’.
- Dr Luis Nacal from the UK ME/CFS Biobank is also talking about the immunology of ME/CFS and updating on the progress of the longitudinal study that had received major funding from the National Institutes of Health (NIH) in America. We hope to also be able to provide a summary update of this key research project in the near future.
If you would like to read more of the ME Association research summaries then please visit the Research section of the website. We also produce a free Index of Published ME/CFS Research that is updated every month and provides a handy guide to all research relating to this disease.
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