The effect of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) severity on cellular bioenergetic function, 2020, Tomas et al

Andy

Andy

Retired committee member
Myalgic encephalomyelitis/ Chronic fatigue syndrome (ME/CFS) has been associated with abnormalities in mitochondrial function. In this study we have analysed previous bioenergetics data in peripheral blood mononuclear cells (PBMCs) using new techniques in order to further elucidate differences between ME/CFS and healthy control cohorts. We stratified our ME/CFS cohort into two individual cohorts representing moderately and severely affected patients in order to determine if disease severity is associated with bioenergetic function in PBMCs.

Both ME/CFS cohorts showed reduced mitochondrial function when compared to a healthy control cohort. This shows that disease severity does not correlate with mitochondrial function and even those with a moderate form of the disease show evidence of mitochondrial dysfunction. Equations devised by another research group have enabled us to calculate ATP-linked respiration rates and glycolytic parameters. Parameters of glycolytic function were calculated by taking into account respiratory acidification. This revealed severely affected ME/CFS patients to have higher rates of respiratory acidification and showed the importance of accounting for respiratory acidification when calculating parameters of glycolytic function. Analysis of previously published glycolysis data, after taking into account respiratory acidification, showed severely affected patients have reduced glycolysis compared to moderately affected patients and healthy controls. Rates of ATP-linked respiration were also calculated and shown to be lower in both ME/CFS cohorts.

This study shows that severely affected patients have mitochondrial and glycolytic impairments, which sets them apart from moderately affected patients who only have mitochondrial impairment. This may explain why these patients present with a more severe phenotype.
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Open access, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231136
 
Funding: This study was funded by an ME Research UK grant to MW. Additional funding awarded to JLN from The Medical Research Council, Action for ME, and the ME Association was also used to fund this study.
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From the discussion section (all bolding mine).
There were no differences between the moderately and severely affected ME/CFS groups for any of the cellular respiratory parameters (Fig 1). This suggests that mitochondrial function of PBMCs does not correlate with disease severity in ME/CFS and even those moderately affected by the disease have an impairment in bioenergetic function. The lack of association between disease severity and mitochondrial function suggests that the previously reported reduction in mitochondrial function in ME/CFS is not due to deconditioning. If the lower mitochondrial functioning reported in ME/CFS was due to deconditioning we would expect to see a significantly lower mitochondrial function in the severely affected cohort who were housebound or bedbound when compared to the moderately affected cohort [24, 25].
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There are several limitations of this study. PBMCs are a very heterogeneous cell population that are comprised of a number of different cell types with different bioenergetic demands [29]. In this study we have used PBMCs rather than stratifying the population out into the sub-populations of cells that PBMCs are comprised of. This was due to the high number of cells required to look at each of the PBMC sub-populations in turn. However, if ethical approval could be obtained in order to collect enough cells to do so, then this stratification would add strength to the study. Future studies should also look at lipid metabolism (which has been shown in other studies to be altered in ME/CFS [30–32]) and whether it differs between the cohorts and how it compares to results seen here in glucose metabolism. The limitation of just investigating glucose metabolism in these cells means that an overall assessment of cellular bioenergetics cannot be made. Valuable information would be gained from repeating these types of experiments and analyses in other cells types in order to see whether these changes are specific to PBMCs or are more systemic. This work would also benefit from being conducted in other disease cohorts with fatigue as a core symptom in order to determine whether the changes in bioenergetics are a marker of the disease ME/CFS or the symptom of fatigue. While clear differences between cohorts have been identified in this study, even when using robust and conservative statistical techniques, higher participant numbers, including samples from multiple international locations, would strengthen the findings.
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ETA: Added 2nd and 3rd quotes.
 
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Sasha said:
I thought we hadn't previously seen good evidence of mitochondrial dysfunction in PwME?

What do you think of this, @Jonathan Edwards?
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I still think that losing at peripheral blood mononiuclearcells is very difficult to interpret. As I have said before, white cells in the blood are more roles by definition not doing anything much - just being transported to somewhere they might do something. If there was a mitochondrial abnormality responsible for ME type symptoms I would expect it to show as shifts in metabolites in tissues like muscle or lever that can be assessed by magnetic resonance spectroscopy.

I find it very hard to assess papers from abstracts these days. For some reason the crucial numerical data are no longer included in abstracts. To me that is bad science, whether it is due to journal fashion or obfuscation by authors.
 
Hopefully me research UK will publish a lay summary. I did t really understand what they were saying about acidification and I think that they Said the severe ME Lowered glycolysis was correlation not necessarily cause. nice to see some decent research coming out of the uk although I assume “larger studies are required”.
I was surprised to see a paper with JLN initials.
It seems respiratory acidification is something to do with carbon dioxide levels?.


Found this, i don’t know relevance https://www.healthline.com/health/respiratory-acidosis
 
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I am uneasy by these researchers using the imo “off key” criteria of nice and icc, to redefine how the severities are classified. These have been at odds with the severity scales and how groups like the 25% define themselves.

I'm not suggesting there's bad intent , it was probable convenience or lack of expertise. The problem with severe ME defined as mostly bedbound, is it decreases the numbers in the severe category (harmful when the general incidence number is often inflated ie the 25% become the 5- 10% and easier to justify the marginalisation)


Afaic it's also inaccurate. Usually severe m.e is divided into upper and lower categories and I think there are thousands of people essentially not mostly, housebound who aren't mostly bedridden.

i also personally understood moderately affected to be not working but able to leave the home most days.
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This post has been copied and several posts moved to this thread:
ME severity scales - discussion
 
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Sasha said:
I thought we hadn't previously seen good evidence of mitochondrial dysfunction in PwME?
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I have yet to read the study, but based on what is earlier on this thread this study is not claiming no mitochondrial dysfunction. Its claiming severity is not associated with mitochondrial dysfunction. This means that the sicker patients have more or less the same mitochondrial function as the moderate patients. Its glycolytic function that makes the difference.

If replicated this could be huge. It implies that multiple energy production pathways are suppressed. It open up new investigatory and treatment targets ... its no longer mitochondria or something else, its mitochondria AND something else.

They really need to do this on cell types other than PBMCs though. That would be an important issue in further studies.
 
alex3619 said:
I have yet to read the study, but based on what is earlier on this thread this study is not claiming no mitochondrial dysfunction. Its claiming severity is not associated with mitochondrial dysfunction. This means that the sicker patients have more or less the same mitochondrial function as the moderate patients. Its glycolytic function that makes the difference.

If replicated this could be huge. It implies that multiple energy production pathways are suppressed. It open up new investigatory and treatment targets ... its no longer mitochondria or something else, its mitochondria AND something else.

They really need to do this on cell types other than PBMCs though. That would be an important issue in further studies.
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I'm sure you recall Karl Morten's study on muscle cells. Karl has been trying to get funding to do more work on this.

Anyone heard anything about the nano-needle?
 
alex3619 said:
its no longer mitochondria or something else, its mitochondria AND something else
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Which to my medically uneducated brain makes me wonder what it might be that could cause damage to more than one aspect of the energy processing? The same cause hitting multiple aspects, but differently for different people? Or maybe it starts with one thing getting hit, and perhaps for some people that then cascading and further damaging other parts of their energy processing system? Possibly due to still-intact aspects being under more strain?

I wonder if there is any understanding if, for those with multiple aspect failures, if all those aspects failed at the same time, or if they went wrong sequentially.

The idea that severity maybe relates to how many different aspects might be impacted is intriguing.

(I know 'aspects' is a poor word choice here, but unsure what the right word is).
 
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meres.uk/CellBioenerg
http://www.meresearch.org.uk/our-research/completed-studies/cellular-bioenergetic-function/

MERUK write up.

They are defining moderate ME as housebound and severe bedridden which I still find problematic as said above.

Unfortunately they don’t expand at all on respiratory acidification. Is it that in severe ME, who they take as bedridden , that the breathing is impaired due to lying on Back, causing an oxygen Co2 issue which explains some of the glycolysis dysfunction but not all?

I note Dr Charles Shepherd has said those longterm bedridden with neurological or rheumatoid conditions, I assume that includes ME, would be at high risk of respiratory complications in covid, someone explained to me that was due to impaired or restricted lung function in bedridden people.
 
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Barry said:
Which to my medically uneducated brain makes me wonder what it might be that could cause damage to more than one aspect of the energy processing?
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Pure speculation, but it looks to me as though its orchestrated, part of an evolutionary response, perhaps in respect to viruses. It hasn't necessarily kicked in all the way with milder patients, but does so when a patient goes severe. There are two questions here ... first, what is the mechanism doing the glycolytic derangement, and secondly what mechanism is orchestrating all this ... what are the details and what triggers it. Again, this is just speculation.

Implications regarding glycolysis are maybe 24 years old now.

What is important here is there is a differential in glycolysis in patient severity stratification. I have other business to attend to so have not read the paper yet.
 
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