Elevated Energy Production in Chronic Fatigue Syndrome Patients

A.B.

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Chronic Fatigue Syndrome (CFS) is a debilitating disease characterized by physical and mental exhaustion.

The underlying pathogenesis is unknown, but impairments in certain mitochondrial functions have been found in some CFS patients. To thoroughly reveal mitochondrial deficiencies in CFS patients, here we examine the key aspects of mitochondrial function in blood cells from a paired CFS patient-control series.

Surprisingly, we discover that in patients the ATP levels are higher and mitochondrial cristae are more condensed compared to their paired controls, while the mitochondrial crista length, mitochondrial size, shape, density, membrane potential, and enzymatic activities of the complexes in the electron transport chain remain intact.

We further show that the increased ATP largely comes from non-mitochondrial sources. Our results indicate that the fatigue symptom in this cohort of patients is unlikely caused by lack of ATP and severe mitochondrial malfunction. On the contrary, it might be linked to a pathological mechanism by which more ATP is produced by non-mitochondrial sources.
Non-mitochondrial sources would include glycolysis.

http://www.jnsci.org/files/article/2016/e221.pdf
 
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adreno

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From the discussion:

Mitochondrial crista architecture is exquisitely and dynamically maintained to support the changing mitochondrial aerobic respiratory rate 26-30. The membrane area and number of cristae are expanded upon energy need elevation to promote respiratory activities 31,32. The fact that the crista number is increased in CFS patients suggests that their energy demands might be unusually high, which triggers condensation of mitochondrial crista membranes.
 

Keela Too

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Edit Apologies - The *less ATP comment below isn't correct

Hmmmm So all the structures for producing ATP are seen in the mitochondria at an elevated level.... but then the graph shows that there is actually LESS ATP in the mitochondria than expected.... why? Are the mitochondria reacting by trying to set up a greater structural production system, but for some reason that isn't working.

The higher non-mito (ie glycolysis) ATP might then be taking up the slack in the production of ATP for the cell.... but this might also produce other metabolites like lactic acid that in turn inhibit functioning?

Not sure... going to see if I can read the paper itself.... lots to think on here.

Edit to add: Seems that the mitochondrial structures ARE in fact operating as expected. Curiouser and curiouser.
 
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Tuha

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Are these findings contradictory to Naviaux´s findings? I saw that some members of the research team are also from Stanford. It would be interesting to know if they cooperate with prof. Davis.
 

Keela Too

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Indeed snowathlete.

I know some have increased sugar appetite. However although I'd like to eat it, I have had some bad reactions to increased sugar, so tend not to crave it any more. (Seriously, I ate an icecream with all the caramel sauces one day with my daughter and felt seriously ick afterwards, shakes the lot. :( )
 

J.G

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Wow, this is unexpected and counterintuitive (to me anyway). If we manage to reconcile these new insights with previous hypometabolic findings we'll make a significant step forward. (And it'll be a textbook case of 'thesis, antithesis, synthesis' at work. I love it. In such quick succession, too.)
 
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Keela Too

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I've sent the paper to my daughter who is doing a biomed PhD currently. Her initial comment (across a mug of tea here) is that maybe there is a block in the metabolic pathway that hasn't been measured? The paper seems to suggest that the Electron Transport Chain is all operating correctly.... but why then is there less ATP in the mitochondria? Is less being produced, or is it getting used up?

Of course these are white blood cells that are being used not muscles, so maybe they are working harder fighting infections or something? (Free-wheeling with ideas now). I wonder what a comparison of muscle mitochondria would look like?
 

alex3619

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This goes to how our mitochondria work. If there is a deficiency (and this does not have to be ATP) due to a functional (as in biochemical) impairment, then there might be structural changes to try to compensate. I would also want to know about non mitochondrial ATP, as in what is the actual source.

Many years ago it was briefly discussed that we might be diverting ATP to nonproductive functions, such as vicious cycles of metabolism. I wonder if there is any connection here. I forget the specifics now, but the idea is we keep moving metabolites round and round and don't actually need them. Another possibility is that a metabolite deficiency has us converting and reconverting the same metabolites, using up ATP, but still not getting enough because its the same pool that is being converted and not enough new metabolites are being synthesized.
 
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Simon

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Julia Newton's muscle culture work indicated the problem was with pyruvate dehydrogenase ie in the cytoplasm so glycolysis seems to be normal, but not neough pyruvate is produced, needed to fuel the mitochondira
 
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Another possibility is that a metabolite deficiency has us converting and reconverting the same metabolites
So could that chime with the Naviaux study? I was feeling encouraged because a few researchers have said they've so far found similar results to Naviaux (is that 4 times? not sure I'm remembering right). This seemed discouraging as to my lay reading it is contradictory, but perhaps reading it wrong?
 

A.B.

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This is needed to determine the tissue distribution. Indeed if it were not unethical and very dangerous, I would want to know about nerve mitochondria as well.
Indeed, one needs to remember that blood metabolomics measures the average of all the body's metabolism. Here they looked at peripheral blood mononuclear cells. Maybe this is a local effect, while the global situation is that of hypometabolism.
 
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alex3619

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So could that chime with the Naviaux study? I was feeling encouraged because a few researchers have said they've so far found similar results to Naviaux (is that 4 times? not sure I'm remembering right). This seemed discouraging as to my lay reading it is contradictory, but perhaps reading it wrong?
Yes, I think 4 times so far, 2 USA, 1 Japan, and 1 Norway. ATP and general metabolites are not the same. Also using ATP to do things will require other things being present, including metabolites. If we are forcing ATP production to try to do things, then it seems the problem may not be mitochondrial, and something is blocking us using ATP rather than making it. That might even be autoantibodies.

Please keep in mind that this finding is new and we need more research.
 
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This is what I was thinking of:
We found four main differences in cultured skeletal muscle cells from subjects with CFS increased myogenin expression in the basal state, impaired activation of AMPK, impaired stimulation of glucose uptake and diminished release of IL6
from http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122982

Is glucose uptake a different process from glycolysis? I may be misunderstanding the processes.