The 12th Invest in ME Research Conference June, 2017, Part 2
MEMum presents the second article in a series of three about the recent 12th Invest In ME International Conference (IIMEC12) in London.
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ME/CFS energy metabolism study by Cara Tomas confirms impairment in mito oxidative phosphorylation

Discussion in 'Latest ME/CFS Research' started by Hip, Nov 8, 2017.

  1. Hip

    Hip Senior Member

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    A study just published in October 2017 by PhD student (and ME/CFS patient) Cara Tomas finds that mitochondrial oxidative phosphorylation is functioning well under par in ME/CFS patients at baseline, and that when ME/CFS patients' cells need to generate extra energy in order to cope with increased physiological stress, these cells are less able to ramp up their energy production to meet the higher energy demands.

    So ME/CFS patients' mitochondria are not able to produce enough energy at baseline, and these mitochondria have additional problems when trying to ramp up energy production when higher energy output is required.

    The published paper by Cara Tomas is here:

    Cellular bioenergetics is impaired in patients with chronic fatigue syndrome

    The Tomas study analyzed in vitro the energy metabolism of ME/CFS patient's peripheral blood mononuclear cells (PBMCs), using a commercial laboratory machine (called the Seahorse XFe96 Analyzer) which is specially designed to measure cell energy metabolism (thus this study should be reproducible by anyone with such a machine).


    Interestingly, although oxidative phosphorylation was impaired in ME/CFS, glycolysis in ME/CFS patients' cells was found to be normal.

    Baseline energy output from anaerobic glycolysis in ME/CFS patients' cells was the same as the healthy control cells; and also the glycolysis stress test (where cells need to ramp up their glycolytic energy production to meet higher energy demands) showed that glycolysis in ME/CFS patients' cells is able to increase energy output when required, just as effectively as healthy control cells.

    So in ME/CFS, glycolysis is working normally at baseline, and is perfectly able to increase energy output when required. Whereas oxidative phosphorylation was found impaired on both counts.



    The findings of this study by Tomas broadly match up with the results of the Myhill, Booth and McLaren-Howard energy metabolism studies, which found that ME/CFS patients have impaired mitochondria oxidative phosphorylation (as well as impairments in the transport of ADP and ATP in an out of the mitochondria, and other impairments).

    This Tomas study I think (but am not sure) would also be consistent with Fluge and Mella's metabolic profiling study. Fluge and Mella's results suggested an impairment of pyruvate dehydrogenase (PDH), which is an enzyme that couples glycolysis with oxidative phosphorylation. When burning glucose for energy, glucose is first processed by glycolysis (situated outside the mitochondria), and then the energy production process is handed over to the mitochondria, where oxidative phosphorylation completes the job.

    With an impairment in pyruvate dehydrogenase, there is a partial blockage in this handover, meaning that oxidative phosphorylation does not get a chance to do its job (so from the Fluge and Mella perspective, in ME/CFS oxidative phosphorylation might be fully functional, but does not get a chance to function properly because it is not handed over what it needs).

    However, oxidative phosphorylation can also burn fats for energy, and fat burning does not rely on glycolysis or pyruvate dehydrogenase, so even if PDH were impaired, it would not alter the fat burning capabilities of oxidative phosphorylation in the mitochondria. So this raises a question mark as to whether in the Tomas study, oxidative phosphorylation was running on the glucose or fat energy production pathway.

    The Tomas study does talk about adding glucose solution to the cells, which suggests that in this study the energy source oxidative phosphorylation is running on is glucose rather than fats. In which case, the impairment that Tomas found in oxidative phosphorylation could be due to an impairment of pyruvate dehydrogenase, making the Tomas study consistent with the Fluge and Mella paper.



    An article about the Tomas study is found here. And a thread discussing an earlier poster presentation by Cara Tomas is found here.
     
    Last edited: Nov 8, 2017
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  2. gregh286

    gregh286 Senior Member

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    Londonderry, Northern Ireland.
    Feels we are getting so close. Narrowing down the broken energy cycle all the time.
    A global abundance of bright minds starting to circle its prey.
    Insulin a PDH complex stimulant.
    But in theory we should be on paleo.
    Pick your poison.
     
    Last edited: Nov 8, 2017
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  3. Jesse2233

    Jesse2233 Senior Member

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    Great summary and analysis @Hip

    Do you think there's a theoretical basis for HBOT (or other oxidative therapies) as a way to kickstart OXPHOS?
     
  4. Hip

    Hip Senior Member

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    I would not have thought HBOT would help with the oxidative phosphorylation partial blockage, because as far as we know, there is no shortage of oxygen being supplied to the mitochondria.

    We don't know exactly why oxidative phosphorylation and mitochondrial functioning is under par in ME/CFS, although Fluge and Mella suggest oxidative phosphorylation issues might be due to pyruvate dehydrogenase impairment, and Prof Behan's original idea says that mitochondrial ATP / ADP transport might be blocked due to ANT autoantibodies.

    But I think the general idea is that there is a blockage somewhere, and that blockage, whatever it might be, is the source of the bottleneck in energy production.
     
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  5. bertiedog

    bertiedog Senior Member

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    Can somebody tell me if the role of NADPH fits in to the difficulty that is showing up of us making insufficient energy? Reason I am asking is that I notice I have several SNPs involving the production and transfer of NADPH which I would have thought would make the situation even worse if there was any involvement.

    Thanks

    Pam
     
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  6. Hip

    Hip Senior Member

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  7. ljimbo423

    ljimbo423 Senior Member

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    Hi Pam- In Robert Naviaux"s paper "Metabolic features of chronic fatigue syndrome" he says this-

    He then goes on to say-

    http://www.pnas.org/content/113/37/E5472.full

    It seems he thinks NADPH is very important to the CDR and mito functioning.

    Jim
     
  8. rodgergrummidge

    rodgergrummidge

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    Once again, a nice summation @Hip !
     
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  9. rodgergrummidge

    rodgergrummidge

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    Oxygen concentration (tension) in human tissues is <5% which is much lower than the normal atmospheric O2 concentration of 20%. So while PBMCs normally have <5% O2, taking them out of the blood and putting them in a seahorse machine puts them in a much higher 20% O2 concentration. Even at the much higher than normal physiological O2 concentrations of the seahorse, PBMCs are still unable to effectively 'burn oxygen' via OXPHOS. Thus, the idea that simply trying to increase O2 concentrations using HBOT to kickstart OXPHOS seems very unlikely.

    In this theory, mitochondrial metabolism is perfectly functional but a PDH defect starves the TCA cycle of AcetylCoA and so there is insufficient biofuel to run OXPHOS. If this was the case, why dont ketogenic diets provide more widespread success in treating CFS? I agree that at least some CFS patients clearly have decreased PDH enzyme activity, but I cant understand why a ketogenic diet doesnt alleviate this issue.

    Lets rename the disease: Conundrum Fatigue Syndrome!

    Rodger
     
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  10. Hip

    Hip Senior Member

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    Some ME/CFS patients have reported good results from ketogenic diets, but others not.

    The answer to your question might be found in the Myhill, Booth and McLaren-Howard energy metabolism studies, which observed not one but several impairments in ME/CFS energy metabolism, including oxidative phosphorylation impairments, but also impairments in mitochondrial translocator protein (aka: adenine nucleotide translocator), which is responsible for ferrying the ATP created in the mitochondria out into the cytosol of the cell, as well as responsible for ferrying the ADP (the spent ATP) back from the cytosol into the mitochondria for recycling.

    So a ketogenic diet might circumvent a PDH defect, but would not circumvent translocator protein dysfunction.
     
    Last edited: Nov 8, 2017
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  11. bertiedog

    bertiedog Senior Member

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    Thanks for that Jim I was sure I had read it somewhere. Not looking good for me as I have these SNPs all over the place in the folate pathways that mentions the production of NADPH is also involved. I believe a lot of them were to do with detoxification and this might explain my tendency to get severe migraines whenever I try and kill off bacteria and also not good with chemical clearance.

    Acupuncture does seem to help the migraines thankfully but I need to have this done fairly regularly to stop the migraines going into a daily pattern.

    Pam
     
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  12. Mithriel

    Mithriel Senior Member

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    The theory behind HBOT is that the amount of dissolved O2 in the interstitial fluid becomes higher so it can get into tissues where the blood vessels are damaged and there is no haemoglobin. It is almost miraculous for wounds and broken bones.

    I have been going for years and it has helped me, but I had MS episodes just before I went and it may have kept those at bay rather than help my ME.
     
  13. alex3619

    alex3619 Senior Member

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    If we think in terms of a block then this makes sense. However if we think of dynamically regulated suppression then any attempt to bypass it risks even more suppression. Its the same for nutritional supps of all kinds that have an impact ... first they work, then they don't. The concept here is setpoint. Under this hypothesis the setpoint needs to be reset.

    Many do report some improvement on a ketogenic diet.
     

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