Mitochondrial complex activity in permeabilised cells of chronic fatigue syndrome patients (2019) Tomas, Brown, Newton, Elson

John Mac

John Mac

Senior Member (Voting Rights)
Mitochondrial complex activity in permeabilised cells of chronic fatigue syndrome patients using two cell types Cara Tomas , Audrey E. Brown , Julia L. Newton and Joanna L. Elson
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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.

Two different cell types were used in these studies in order to assess individual complex activity locally in the skeletal muscle (myotubes) (n = 6) and systemically (peripheral blood mononuclear cells (PBMCs)) (control n = 6; CFS n = 13). Complex I, II and IV activity and respiratory activitysupported by fatty acid oxidation and glutaminolysis were measured usingextracellular flux analysis.

Cells were permeabilised and combinations of substrates and inhibitors were added throughout the assays to allow states of mitochondrial respiration to be calculated and the activity of specific aspects of respiratory activity to be measured.

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 (p ≥ 0.190) or PBMCs (p ≥ 0.065).

This is the first study to use extracellular flux analysisto investigate individual mitochondrial complex activity in permeabilised cells in the context of CFS. 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.
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https://peerj.com/articles/6500.pdf
 
If this is correct then it fits with quite a lot of other data. Our mitochondria are not working, but are not damaged, though this has been observed before. So, for example, the issue could still be local hypoxia, or PDH inhibition, or signalling factors, as others mentioned above.
 
measured using extracellular flux analysis.

I have often wondered if the extracellular matrix is somehow involved, particularly the amorphous component.
 
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.
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roller* said:
what could this be ?
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Reminds me of Ron Davis' belief of there being "something" in the blood serum. Some molecule for which I think he had an upper or lower boundary on its size. If it's not present in healthy serum, I wonder if such a thing might be regarded as a sort of "poison"/"toxin" - perhaps some molecule usually confined to the gut. Just speculating.
 
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Forbin said:
Reminds me of Ron Davis' belief of there being "something" in the blood serum. Some molecule for which I think he had an upper or lower boundary on its size. If it's not present in healthy serum, I wonder if such a thing might be regarded as a sort of "poison"/"toxin" - perhaps some molecule usually confined to the gut. Just speculating.
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Absolutely, and a similar experiment has been repeated by Dr Karl Morten, as briefly reported by the ME Assocation, here.
Dr Morten revealed how when examining mitochondrial function, they took blood plasma from ME/CFS patients and added it to healthy muscle cells, and this resulted in a startling effect on the cells ability to absorb oxygen. They are continuing with work in this area and hope to determine why the energetics of the cells are affected in this way.
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John Mac said:
https://peerj.com/articles/6500.pdf
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So, if I understand correctly, and as others here have alluded to:

1. The mitochondria themselves aren't broken: good. These researchers took the lid off the mitochondria and tested out the machinery and found it all to be operating normally.

2. Yet, mitochondrial function in whole cells is *abnormal*. The researchers suggest this points towards a problem upstream of the mitochondrial respiratory chain (question: is this synonymous with 'electron transport chain'?). Would this be a problem with substrates getting into the mitochondria? The researchers specifically mention oxygen transport, but O2 saturation is normal when measured by finger pulse oximeter. So, is something blocking oxygen from getting into the mitochondrion? Something... in the blood!...
 
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hinterland said:
The researchers specifically mention oxygen transport, but O2 saturation is normal when measured by finger pulse oximeter. So, is something blocking oxygen from getting into the mitochondrion? Something... in the blood!.
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It doesn't have to be a "mysterious something" (although it could); something they don't see or understand (because, e.g., the nano-needle is not made for it), like different signals for example, or an altered signal which would be needed for activation of enzymes in the mitichondria. Or a protein. Or...

Just one possible example (there are certainly more): It is known that calcium in the mitochondrion is needed to activate several enzymes and to ensure O2 consumption, which are needed for ATP production. If this calcium (signal and ions) is missing, not all enzymes are activated (like PDH), AMPK production increases and O2 consumption of the mitochondria decreases.
 
roller* said:
myhill, davis, morten may have seen something infectious/invading.

would the plasmapheresis from scheibenbogen/berlin have filtered out such a thing or was this treatment supposed to do something different?
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They have an idea of the molecular size and its much smaller than a virus, its in the protein range. It might not be protein though, as even things like lipopolysaccharides can be very large.

PS However a pathogen might still be making it.
 
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roller* said:
would the plasmapheresis from scheibenbogen/berlin have filtered out such a thing or was this treatment supposed to do something different?
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This treatment has an autoimmune background. If I understood and remember correctly, they selected patients with high values in the CellTrend panel, i.e. autoantibodies to certain muscarinergic and adrenergic receptors.
 
Mij said:
We need to stop searching for pathogens, they've been ruled out at nauseam. We need an AMPK ME recharger at every 3km. Perhaps Ron Davies could develop one? Similar to electric car rechargers.

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Pathogens have definitely not been ruled out. We don't know much about the vast majority of pathogens out there and some pathogens previously thought to be harmless are being found to have possible disease-causing mechanisms in some people.

A study published last year in Nature suspects EBV (or was it a Herpes virus?) to be a possible cause behind several major autoimmune diseases.

Here a virus previously thought to be harmless could be a cause of encephalitis: https://www.folio.ca/u-of-a-scientists-discover-a-hidden-cause-of-encephalitis/.
The finding identifies a pathogen named pegivirus as the culprit, and deepens scientific understanding of what leads to the neurological disease. It’s hoped the discovery opens new avenues of research for potential therapies.

“This virus was not known to cause any disease,” said Christopher Power, Canada Research Chair in Neurologic Infection and Immunity at the U of A and senior author of the study. “In fact, most people with pegivirus won’t get encephalitis, but we now know that it affects some people uniquely.”
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Recent research shows growing evidence for "inactive" viruses having an impact on the immune system because of free-floating RNA. The viruses aren't replicating in an active infection and could still have a disease-causing effect.

Pathogens are far from having been ruled out. Researchers working on the microbiome find entirely new viruses and bacteria regularly, they barely need to try, there are so many of them.
 
Mij said:
We need to stop searching for pathogens, they've been ruled out at nauseam. We need an AMPK ME recharger at every 3km. Perhaps Ron Davies could develop one? Similar to electric car rechargers.
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lansbergen said:
Not the one I suspect
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perhaps, its not one culprit. its not aliens. its a crime scene.
...or like riddles in the fairy tales: "its not the gut, but its the gut".

maybe our world view is hindering to proceed.
perhaps, the best investigations so far came from "math" (statistics) ?
 
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