As time has gone on, the energy production issue in chronic fatigue syndrome (ME/CFS) has become better and better documented as researchers take different slants on it.
Multiple studies, taking different slants, have found energy production problems in ME/CFS.
Take the whole body energy production tests. Workwell’s two day cardiopulmonary exercise tests (CPETs) have documented the damaging effects that exercise one day has on ME/CFS patients’ ability to produce energy the next day. Harvard pulmonologist David Systrom’s invasive CPETS have located multiple areas of deficiency (poor oxygen uptake, microcirculatory problems, reduced preload) in energy production. From Katarina Lien in Norway, to Betsy Keller in the U.S., to Vermeulen and Visser in the Netherlands, many studies suggest that fundamental problems producing energy exist. (We await the results of one of the most intriguing studies: Avindra Nath’s CPET/metabolic chamber study.)
Then there’s the whole body metabolism slant. Metabolic profiling using metabolomics has provided another way to demonstrate that something in the energy production process has gone awry.
Then there’s the cellular energy production slant. Rahim Esfandyarpour and Ron Davis’s nanoneedle tests seem to suggest that a breakdown in cellular energy production occurs when ME/CFS patient’s cells are put under stress. Missailidis and the Fisher group in Australia have identified abnormal complex activity in the mitochondria. The Newcastle group has specialized in cellular energy production – and they always seem to find intriguing and different ways to test it.
This is by no means a comprehensive overview of energy production studies in ME/CFS. The point is that problems in energy production seem to crop up in whatever compartment ME/CFS researchers have looked in.
The Study
The Gist
- No matter how they’ve looked at it – whether using exercise tests, metabolic profiling or cellular stress tests – studies have found energy production problems in ME/CFS.
- For the second time Cara Tomas and the Newcastle group threw ME/CFS patients cells into the Seahorse machine – and tested how well they produced energy.
- For the second time the group got much the same results: both glycolysis (anaerobic) and the TCA cycle (aerobic) worked just fine!
- Reduced glucose metabolism, though, suggested that people with ME/CFS were not using their most efficient energy source effectively. Their cells were, as other studies have suggested, turning to amino acids for fuel.
- While the glycolysis and aerobic energy production systems seemed to be working fine, one aspect – the conversion of pyruvate (the outcome of glycolysis) into acetyl CoA – the starting point of the TCA cycle – appeared to be impaired. This could have quite negative consequences as the TCA cycle provides the vast majority of the ATP we rely on.
- The fact that the group has now found similar energy problems in two very different cell types (immune/muscle cells) suggests the energy production problems in ME/CFS may be everywhere.
- The authors proposed that the energy production problems in ME/CFS cells were likely genetic or epigenetic in nature.
- Problems with hydrogen sulfide metabolism could play a role: a blog on that is coming up.
The Newcastle group has done this kind of analysis before on immune cells called PBMCs (peripheral blood mononuclear cell). That study found that put under stress, the immune cells were unable to produce as much energy as cells from healthy controls.
In 2015, Newton found that when stimulated, muscle cells from ME/CFS patients demonstrated impaired activation of AMPK – the protein kinase which stimulates the cells to uptake the glucose and fatty acids it needs to produce energy. Impaired stimulation of glucose uptake was found as well. The cells, then, were not getting the substrates they needed to produce energy.
The next study, though, suggested that AMPK wasn’t likely the problem – the problem was something upstream of it. This time, the group took perhaps the most energetically challenged of all cells – the muscle cells – and tweaked them in different ways while putting them through their paces in the Seahorse.
The question they attempted to answer was where the blockade in energy production occurred, and if the energy production problems they found in the immune cells extend to the muscles; i.e. are they likely body-wide?
Like many of these studies, this was a small study – just 20 people – and thus the results must be considered preliminary.
Results
First, some background:
- Glycolysis results in pyruvate (and yields 2 ATP (per molecule).
- Pyruvate is then broken down into acetyl-CoA.
- Acetyl-CoA is the starting point for the citric acid or TCA (or Krebs cycle).
- The TCA cycle produces most of our ATP (yields 30-36 molecules of ATP in the TCA cycle).
Glycolysis was working fine.
The Seahorse is able to test both parts of our energy production cycle independently. The study suggested that the muscle cells of ME/CFS patients have problems utilizing glucose, but glycolysis was working fine; i.e. when the glycolytic cycle was given glucose, it was able to convert it into pyruvate at a good rate..
Tests of the mitochondrial respiration (cycle citric acid, TCA or the Krebs cycle – all refer to the same process) using galactose and fatty acids) suggested that it was able to punch out ATP at a good rate: it was working fine.
If glycolysis and the TCA cycle are working fine, then where was the problem?
If I got it right, the problem appeared to be in the intermediary between the two – where pyruvate – the end point of glycolysis – is transformed into acetyl-CoA – the beginning of the TCA cycle. That suggests that either the pyruvate dehydrogenase complex (PDH) – which transforms pyruvate into acetyl-CoA – is breaking down, and/or pyruvate dehydrogenase kinase (PDK) – which inhibits PDH – is acting up.
Fluge found evidence of increased PD kinase activity – which could be stopping PDH from metabolizing pyruvate to acetyl-CoA.
The possibility of a defect in the pyruvate dehydrogenase complex (PDH) brings us back to Fluge’s mammoth 2016 study, “Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome“. That study, coming from an entirely different angle, pinned the blame on the PDH complex as well. Fluge’s 300-person metabolomics study found that reductions in amino acids that fuel the TCA cycle suggested that the PDH enzyme was not converting pyruvate to Acetyl CoA.
This problem, interestingly enough – given the results of last year’s study suggesting that too much lactate is being produced during exercise in ME/CFS – would result in an accumulation of pyruvate and an overproduction of lactate. (Lactate is produced from pyruvate.)
A reduced breakdown of pyruvate – which ultimately comes from glucose – results in the increased usage of ketogenic amino acids (fats, amino acids) in the TCA cycle. (That could explain why ketogenic type diets are helpful for some people). Fluge also found increases in the expression of pyruvate dehydrogenase kinases and the SIRT4 enzyme – both of which shut down PDH.
PDK, interestingly, ramps up its activity during times of starvation in order to limit energy usage. It’s intriguing how many different time concepts like ‘starvation, hibernation and hypometabolism” have been used in ME/CFS.
Lastly, the authors asserted that the study results indicate that the problems with the mitochondria are likely either genetic or epigenetic in nature.
Conclusion
Twenty years of research from ME Research UK!
If I read it right, this study, then, suggests two major problems are present: ME/CFS patients’ muscles cells are not utilizing glucose well, and there’s a problem converting pyruvate to Acetyl CoA.
We’ve heard about the problems with glucose before. Glucose – the quickest, most efficient energy source – is apparently being replaced, to some extent, by less efficient amino acids and fats as an energy substrate.
If pyruvate is not being properly metabolized to acteyl CoA, it will show up in the form of increased lactate levels – which a study by the Fluge group found last year.
Since the Newcastle group has found these problems in both the immune and muscle cells (and those cells are nothing like each other) this study suggests these energy production problems likely show up in many cells and is body-wide.
So, we have yet more evidence – albeit in a small study – of impaired energy production. While we can’t tie the results of all of the energy studies together yet and say, “this is the source” of them, it’s remarkable how many different ways it’s been shown.
On that note, a “new” possibility has recently popped up. It’s actually not a new possibility – in fact, it may be one of the first explanations to show up in the ME/CFS literature involving the mitochondria. In “Hypothesis: Chronic Fatigue Syndrome, Mitochondrial Hypo-function, and Hydrogen Sulfide”, in 2007 Marian Lemle proposed that altered levels of hydrogen sulfide (H2S) could be involved in the energy production problems in ME/CFS. Her thesis is now being investigated by Bindu Paul, a Johns Hopkins researcher. Marian pointed out back then that alterations in H2S can increase blood lactate concentration and altered lactate/pyruvate ratios – resulting in more anaerobic glycolysis. (A blog on H2S and ME/CFS is coming up.)
It’s great to have these creative researchers at work, but we should note that this work doesn’t come for free, or cheaply, and this mitochondrial work was entirely community-supported, in this case by ME Research UK, which is celebrating its 20th year of funding ME research. Let’s celebrate them and thank them for funding this intriguing study and all the others.
Thanks Cort, your commentary on pervasive energy production problems is a great read. If only this sort of cross-study consideration directed research funding globally.
It seems like such a fertile. Just think if the NIH decided to do a funded RFA (Request for applications) just on energy production in ME/CFS….
Perhaps the Nath study will give them the impetus to do that.
omg let’s hope!! and i echo this THANK YOU Cort!
Right on the dot. so many groups doing the same thing and with a low budget and spread of budget, it feels as though we are playing catch 22.
Thanks again Cort. I wonder if the same mechanism that fragments the mitochondria signals pdh to turn down during that process. Looking forward to the NIH results too. This all feels like the disease will be reversible.
Right! I forget all about Prusty – another mitochondrial angle!
what you mean dear Cort
Prusty will come up in few days with his newest results
greetings from Germany
I don’t know anything about the hydrogen sulfide aspect and am looking forward to your article. You might be interested in this new study that suggests treatments for a genetic mitochondrial disease where the mitochondrial enzyme that breaks down hydrogen sulfide is broken. They sound like they have been looked at with me/cfs too?metronidazole, hydroxycobalamin (sp?) https://pubmed.ncbi.nlm.nih.gov/32160317/
Thanks Chris, Looking forward to checking it out. H2S is surprisingly interesting.
H2S is crucial to hibernation in mammals. It can be used to make mice hibernate
Replying to Chris – the hibernation angle sounds interesting, given that one hypothesis of ME/CFS (or my take on it anyway) is that the body is trying to shut down into a kind of involuntary hibernation or dauer(?) state, perhaps in response to a series of, or to individual, stressors/ assaults/ unfavourable conditions, or what it perceives to be such, as a survival mechanism, paring all activity back to the bare essentials to maintain life.
I like to look at disease from the point of view of the body’s logic – what it’s basically trying to do – as the physicist Prof Paul Davies has done in order to to get a fresh new take on cancer.
Otherwise we might just endlessly throw treatments at different problems arising from the primal cause, without ever getting down to the fundamental issue of WHY it’s happening, and addressing that.
Thanks Cort. Excellent as usual. What are the speculations on what the epigenetic causes might be and do chronic infections or inflammation take you there? And then… of course… what to do about it
I’ve been looking deeper into this paper (Substrate utilisation of cultured skeletal muscle cells in patients with CFS by Cara Tomas, Joanna L. Elson, Julia L. Newton and Mark Walker).
Those around here some longer know I do believe we have a serious ROS generation problem. When this paper states that our muscle cells don’t produce more ROS then healthy control cells I get confused. I sure can be wrong but I just don’t feel it.
When looking into that paper, one remarkable and puzzling thing pops up: figure 5. It shows the ROS production with glucose, galactose and palmitate (fatty acids). The measured ROS production is !5! times as high when the cells are fed fatty acids versus when they are fed glucose or galactose. I’ve seen these results before but I had to recheck that.
* It is odd for more then a few reasons. Keto-diet lovers claim that using a very high fat low carb diet reduces oxidative stress (and inflamation).
* When the researchers use pure palmitic acid as it seems to be, it is fairly cleanly decomposed to plenty of acetyl-CoA and one ketone coming from the end of the fatty acid chain. That ketone part should also be transformed and end up as acetyl-CoA in the mitochondria.
=> Basically BOTH glucose and fatty acids should end up identical as acetyl-CoA in the mitochondria YET if this same acetyl-CoA comes from fatty acids then measurments indicate that ROS generation is FIVE times as high compared to when glucose is used as a source of the acetyl-CoA.
I hope you frequently feed back your deliberations and ideas to the omf djeurgen.
This baffled me. It sort of couldn’t be right. Yet these are measurement results by a good research team with good tools. Then I remembered “my old love” the Wikipedia(Pentose phosphate pathway). This a parallel pathway to convert glucose to pyruvate (or better said one of it precursors glyceraldehyde 3-phosphate that is also an intermediate in glycolysis) and optionally some other byproducts. A big difference between glycolysis and the pentose phosphate pathway however is that the first produces NADH and the second NADPH.
NADPH is the stuff needed to recycle the all important anti-oxidant gluthathione. Without glucose (or other carbs that can be converted to glucose) as a fuel source for the cells, NADPH production dwindles a lot and with it gluthatione recycling. That leaves the cells in a far more prone state for cleaning up oxidative stress.
When the cells are only fed fatty acids, they would lack much of their ability to make “superb anti-oxidant recycling product NADPH” and hence be far more vulnerable to oxidative stress. That could IMO explain why the measured oxidative stress is so much higher when the cells are fed *only* fatty acids.
Still when feeding the cells pure glucose, both ME and healthy control cells do produce roughly the same amount of oxdiative stress. So both ME and healthy cells are able to produce enough “anti-oxidant recycler NADPH” or in other words to fully use the pentose phosphate pathway to suppress oxidative stress to good levels. So that couldn’t be a main difference between ME cells and healthy cells could it?
Well, unless… …our cells used way less glucose then fatty acids then healthy cells.
The data in the paper doesn’t seem to indicate that so clearly. Yes, our base mitochondrial consumption of glucose is reduced as well as our maximum consumption of glucose. The difference is clear between ME cells and healthy cells, but I wouldn’t call it outright extreme. Our base and maximum fatty acid consumption is comparable to that of healthy people. So one could assume our cells use both at rest and at maximum capacity some more fat versus glucose then healthy cells, but the difference wouldn’t seem to be THAT extreme in my mind.
That however neglects one thing: the tests in the paper are results for either PURE glucose as a fuel or PURE fatty acids. If the cells wanted to produce any ATP (and survive) they HAD to use the only available source of energy. Now if both are available and one source of fuel seems so much easier to use then the other one, why would the cells and mitochondria really bother much to use the more difficult to use source much at all even at rest? It’s like if you had the both gas and coal available to fuel your car, why would you bother convert the coal to gas to drive your car? Yet, if you really had only coal plus the tools to convert it go gas, you’d use coal and the war would drive too.
If the mitochondria can get most of their needs from fatty acid oxidation at base, why bother trying to get pyruvate into themselves and convert it to acetyl-CoA if the necessary enzyme PDH seems to be blocked?
That could vastly skew real life energy usage in ME cells FAR more to fatty acids (and amino acids) then at first or second reading of this research indicates.
If so, then the percentage of glucose in total mitochondrial energy consumption would be reduced a lot. That would also reduce the amount of glucose that has to go through the combined glycolysis plus pentose phosphate pathway a lot. If glucose wouldn’t be massively shifted away from glycolysis to the pentose phosphate pathway then there would be a clear risk of having too few NADPH / recycled glutathione per energy production. *IF* so, that could reduce ROS clean up a whole lot *in real life* where cells have access to a mixture of fuels.
=> It might be VERY interesting to have a research redo the ROS measurments for a mixed glucose / palmitate substrate. If I get it correct this could be done with the Seahorse machine. *IF* the ROS result would differ a lot with this mixed fuel (while they don’t with pure fuels) then that would tell a very important storry IMO!
=> Both the result from the paper: no extra ROS production in ME cells *when fed pure single component fuel* AND the idea of many patients and researchers that ROS is an actual strong problem in ME patients might both be true.
I know this still doesn’t explain why keto-diet are *suposedly* anti-oxidant diets. They use plenty of fat right? But they are largely *ketonic* diets, hence the name. And ketones are rather good anti oxidants by what I’ve learned before. Plain fatty acid consumption with acetyl-CoA as a main component IMO isn’t.
dejurgen,
does the test used
in the comparison
have the ability to have the cells
do ‘work’ vs at rest?
how could cells be ‘forced’ to work? electric stimulation? or how? so that at work vs rest changes could be seen?
They use chemical stimulation. They provide a synthetic chemical in the cell substrate (liquid “fed” to the cell) that pushes the cell to work a lot harder to do more work.
That is a fairly rough simulation of what happens when the cells get actual electric stimulation pulses. That choice is due to the limits of the Seahorse machine used unmodified. It’s up to the manufacture to provide and certify new abilities, not up to the researchers.
From the Tomas and Newton study:
“When using glucose as a cellular substrate we treated skeletal muscle cells with two AMPK activators—compound 991 and metformin. Compound 991 (which is yet to be tested in clinical trials in humans) is a direct AMPK activator12. Compound 991 treatment appears to bring the OXPHOS levels of CFS patient cells up to the same level as untreated control cells. It is unclear whether this effect would extend to cells undergoing exercise in vitro using electrical pulse stimulation (EPS) as there is currently no way to incorporate EPS within seahorse experiments.”
Now let’s step things up another bit: could (excessive) oxidative stress inhibit PDH? If so, inhibited PDH could create more oxidative stress, and that in turn could create more ROS and keep PDH inhibited. That would be some vicious circle.
So I looked up the combination of PDH and several things possibly indicating high oxidative stress. I did found a paper titled ” Protein S-glutathionylation alters superoxide/hydrogen peroxide emission from pyruvate dehydrogenase complex”
from Marisa O’Brien, Julia Chalker, Liam Slade, Danielle Gardiner, Ryan J Mailloux. It says “Collectively, our results demonstrate that the S -glutathionylation of Pdh alters the amount of ROS formed by the enzyme complex. We also confirmed that Ogdh is controlled in a similar manner. Taken together, our results indicate that the redox sensing and ROS forming properties of Pdh and Ogdh are linked to S-glutathionylation.”
IF I get it correctly, that’s complex talk for saying that if oxidative stress changes, the working of PDH (and another key enzyme) changes.
I had to look it up again as it has been some time. A paper titled “Chapter 23 – NO Signaling Defects in Hypertension” from Ingrid Fleming says “While eNOS S-glutathionylation in vitro or in vivo has been triggered by high levels of glutathione disulfide (GSSG) or oxidative thiyl radical formation.”, *indicating* *if* I get it correctly, that it is this oxidized form of glutathione that causes chemicals to be glutathionylated.
If so, that opens the possiblity that too much oxidized versus reduced glutathione (a situation that would easily arise after chronic high oxidative stress) would glutahtionylate / alter / inactivate the PDH enzyme. That in turn (if bad enough) could increase fatty acid versus glucose utilization by the mitochondria a lot. That in turn could result in less glucose going through the pentose phosphate pathway. That in turn could result in more oxidized glutathione versus reduced glutathione. That then in turn could (further) keep PDH inhibited…
=> Could this be part of our vicious circle?
Note: the above linked paper links glutathionylation of eNOS to things like inhibited NO production (a thing that constricts blood vessels and reduces blood flow), endothelial dysfunction, faulty vasso-relaxation…
A paper titled “Chapter 7 – Neural Control of Sleep in Mammals” from “Dennis McGinty and Ronald Szymusiak” links oxidized and reduced glutathione to sleep regulation and patterns.
Note: a “translation” of the above to “English” may or may not folow once or if I get uncrashed from this effort in time:
Note: if text above got mangled: getting my thoughts formed and written is more then enough to crash me.
I find it interesting that acetyl CoA is also required for steroid synthesis, melatonin synthesis and acetylcholine synthesis (too much acetylcholine linked with trigger points in muscles).
There is also a link between acetyl CoA and hydrogen sulphide.
Thank you – such an interesting read. Further to your most recent posts, am compelled to add a frustration here, from a person with ME/CFS (me) re medical/science practitioners not/having the time/money to listen/ing to the (wealth of) information people with ME/CFS have to contribute. I was saying decades ago that, no matter how much I ate, it was like I couldn’t get energy into my cells, well before I had ever heard of the word mitochondria or the Krebs cycle, etc.
Karina…Yes!! I distinctly remember telling my PCP that I didn’t think my food was doing me any good. This was several years before I got full-blown ME/CFS (triggered by EBV). Makes me wonder if I might have had it before. Sooo many questions…
I also remember telling another PCP after I got sicker that I thought something was wrong with my mitochondria. This info was coming from my love of science and teaching elementary science for 26 years. So, very basic knowledge. If I suspected the mitochondria to be the cause, it blows my mind that today’s science is taking so long to find answers.
Thank you again! Hm, interesting and also good to have yet new papers on the same theme. My problem is that I get lost in the details and miss the overall picture. How do these results relate to neuroinflammation? To autoimmunity? To the metabolic trap? Are these different models to explain ME or are they parts in/of a bigger picture?
Also! Here they suggest that it might be a epigenetic or genetic component, and other studies have implicated that too.
I get lost in the bigger picture when talking about the details, even if I understand (in my little understanding) them. Do anyone have a link to or any thoughts themselves about how the bits and pieces fits in the big picture? That is including these newer data and speculations on causes?
I believe my questions are about as confusing as how I feel !
I have Ehler Danlos and one of my first symptoms and what ultimately led to the end of my career was this teach a 4 hour class and then be down for 2 days! Before this I was working 80 hour weeks hiking and biking etc — something I believe genetically was switched on —
I also have Ehlers-Danlos and suffer some of the same kinds of energy deficits: eating even simple carbs doesn’t relieve my fatigue and during exercise my muscles burn like I was climbing steep mountains at high altitudes. This makes me think I’m not getting enough oxygen into my muscles and, from what I read in Cort’s blog here, hints at possibly low blood volume. To counter that, I started taking serious electrolytes (WHO formula) and found this quite effective in preventing the drastic muscle burn.
Hi Angelika, How often do you drink the WHO water? I’m lying in bed with a crash and wondering what to do. I bought some a couple weeks ago.
The study of Newton et al. Is interesting. Why? They have grown those cells outside the body. The results of her tests are therefore free of dysfunctional thoughts of ME / CFS patients. What do the psychologists have to say about that?
Sooooo, much does seem to play on genetics and then on epigenetics. Whether or not the predisposition genetically gets turned on. What triggers that? Some of us can find our links while others can’t. Makes it a pretty individual journey. But it does seem the pathways and dysfunction of them can be figured out. But then the tweaks to “fix” them is pretty individual. As what may work for me, may not for someone else. It could be that the malfunction for me is in a different part of the pathway and/or because of other genetic and epigenetic changes I will have to work around it in a different way. Why I keep saying there won’t be one “fix” for the masses. It has to be an individually tailored “fix”. As science progresses, more is being learned. And it is good to know that even “IF” something got flipped on (like a toggle switch) getting the right combo could very well “switch” things back off.
I was interested to read that we turn to amino acids to get energy. The biggest boost in energy I ever had was when I started taking phenylalanine (an amino acid). I had relatively good energy for a few years. However, a chest infection brought about a downturn in energy, and then doing too much last year helping a friend has done more damage. I am back to rest, rest, rest while hoping for some recovery.
I also used phenylalanine to get an energy boost prior to full on disability. And I’d noticed that I didn’t tan in the sun – a link to tyrosine (melanin production). Since disability, I’ve noticed that if I become blue, I need a little of either. I don’t see it helping much with physical energy any longer, but it does seem to have a positive affect on my brain.
First attempt to “translate” what I have previously written to English.
When reading the “Substrate utilisation of cultured skeletal muscle cells in patients with CFS” from Cara Tomas, Joanna L. Elson, Julia L. Newton and Mark Walker it is VERY easy to read that there is no meaningful difference at all in ROS production between ME and healthy control cells.
The measurement results are clear: “ROS production was measured in the presence of glucose, galactose and palmitate:BSA (Fig. 5). In all three substrates we showed that there were no significant differences between the production of ROS from CFS skeletal muscle cells and healthy control skeletal muscle cells (p ≥ 0.390).”. The graphs are clear too: the study did not reveal ANY meaningful difference in ROS production between ME and healthy control muscle cells.
=> One would say “End of the line for the idea that our muscle cells produce excessive ROS, that idea is death”, wouldn’t one? There could still be too much oxidative stress from an overactive imune system producing plenty of it (as a weapon against pathogens), but muscle cells? No, they don’t produce more ROS neither at base load nor at peak load. If tests on other (non immune) cells would confirm that, then we could safely close that research route and sort of drop the key into a sink hole wouldn’t we?
Yet, to me this idea feels so unnatural. There are many, admittedly indirect, indications pointing to excessive ROS being problematic in ME. Also, many of my personal ideas build on that notion.
When looking a few more times at figure 5 in that paper, we can see that excessive muscle cell ROS may be hidding in plain sight: ROS production when feeding the cells pure palmitate (a fatty acid) as a fuel source creates FIVE times as much ROS compared to feeding the cells pure glucose or pure galactose as a fuel.
How much ROS cells fed with a mixture of glucose and fat would produce is hard to guess, but let me say it is reasonable to assume that when having a mixture of 99% glucose and 1% fat that the ROS production would be very close to that of feeding the cells pure glucose, and that when having a mixture of 1% glucose and 99% fat that the ROS production would be very close to that of feeding the cells pure fat.
How the curve is shaped in between those points? Hard to say, but likely easily enough to measure with the Seahorse machine for both ME and healthy cells. This said, I think it’s fair to say that cells that would heavily lean to fat consumption as a source of their fuel might produce a lot more ROS then cells that would more heavily lean to glucose consumption as a source of their fuel.
=> As one of the conclusions of this research is that glucose (and galactose too) consumption has a major hurdle in the mitochondria (by PDH largely being crippled), it is IMO an almost natural conclusion that we lean more heavily to fat consumption as a source of fuel for our cells.
=> With such, depending on the exact shift towards fatty acid consumption and how bad that shift affects ROS production, it COULD read as plain as this: ME patients muscle cells likely DO produce plenty more ROS then healthy patients when the cells are given a mixture of glucose and fat as a fuel source.
=> Measuring only the extremes of feeding the cells either pure glucose, pure galactose and pure fatty acids may hide the oxidative stress problem in plain sight as that is NOT what actual muscle cells will see.
When looking at figures 4C and 4D in that research paper, we see that our cells can produce 100% of our energy needs by consuming fat and that they can produce twice as much energy as needed during rest by consuming only fatty acids as a fuel source. ME cells seem to be better able or possibly “adapted” to have higher maximum fat usage for energy production then healthy cells.
When looking at figure 2, we see that our mitochondria have plenty and plenty of spare capacity to replace all glucose consumption at rest by fat consumption for energy production. At the same time we see that we have clearly a lot less base and maximum mitochondrial capacity to use glucose as a source of energy then that healthy people’s muscle cells have.
=> With a major enzyme (PDH) making carb consumption by the mitochondria a lot more difficult and having at the same time more maximum capacity to consume fatty acids as a fuel, it is easy to see that our ME muscle mitochondria may turn very quickly to a way higher portion of their energy production obtained by burning fat versus what healthy muscle cells would do.
=> The above conclusion is exactly in line with what the paper says, with one key twist: that shift MIGHT, as in that needs to be confirmed by Seahorse machine experiments, lead to oxidative stress generation closer to the X5 seen with pure fat usage then then X1 seen with pure glucose or galactose usage.
Compare it to this: WWII fuel shortage has demonstrated that cars can drive with wood block combustion. Some Discovery Channel TV shows have shown it is possible to convert a normal gas fueled car to either a pure wood block fueled car or a duel fuel gas and wood block car.
Now imagine having such dual fuel car and living in a place with both access to convenient gas or plenty of free wood blocks you need to chop in your own forest. Would you chop trees and dry and cleave them and burn them in the pick up wood gasifier even if it were cheaper then buying gas if you didn’t need the money desparately? I wouldn’t, as it’s such a hard thing to use the wood as a fuel source. So why would our mitochoindria not turn mainly to fatty acid consumption if the usage of glucose is so difficult in our cells?
@dejurgen please share your thoughts with the authors of the papers you cite. Your thoughts are clear enough- just copy and paste what you have written here. Give them a chance to think about and perhaps even do what you suggest.
I wont do that myself. My experience as a former non-medical researcher is that many researchers are very weary of outsiders contacting them with (!their own!) research ideas. They are often quite less weary of outsiders pointing them to ideas of other people.
If you do not gradually build contact with them and build toward not only providing an idea but also a way to fund and colaborate, they easily see multiple obstacles as what does that person (the person who came up with the idea) expect in return, who will have legal ownership of the results, publications or credit, how will cooperation be build into our ongoing projects or future project proposals…
Me contacting them can either further the idea or hinder them from working with the idea if it runs into how they (have to) work.
So therefore, if someone like you or Cort finds this idea to make really sense and believes she or he has the credibility to contact this research group, then please point them to this blog and these ideas. I do not need any form of official cooperation or credit even if this idea would be new to them. Then it would be nice, but not required, to have them give some sort of credit to where the idea came from. But to me, getting science and our health forward is more important then my ego.
As written in the difficult first texts, this 5X difference in ROS generation baffled me at first. It looked like being surreal and near impossibly correct.
Both glucose and galactose can however be fed into the glycolysis cycle. The start and end of the glycolysis cycle however are shared with the pentose phosphate pathway. Simplyfing things, the pentose phosphate pathway is very important for recycling oxidized glutathione. Oxidized glutathione can no longer clean up oxidative stress. It needs to be recycled.
When our mitochondria would prefer to use only very few carbs as a source of fuel, then the need to produce pyruvate from glucose or galactose would be a lot lower as using pyruvate is what our cells do when using carbs. With that, our cells would have to convert a lot less glucose and galactose to pyruvate. That in turn would reduce the amount of carbs entering the sum of both the glycolysis and pentose phosphate pathway a lot. That would risk to lose a lot of our cells natural way to recycle the all important glutathione.
If the mitochondria “would keep refusing to use more pyruvate”, then the cells could either:
* shift a lot more glucose (or better said the conversion of glucose to pyruvate) away from glycolysis and through the pentose phosphate pathway
* just use the combined glycolysis and pentose phosphate pathway a lot more then for whatever small amount of pyruvate the mitochondria seem to demand.
The second option of coarse would lead to pyruvate piling up and not being consumed, a bad thing as pyruvate piling up too high is rather toxic. The obvious solution here would be to convert this excess pyruvate to lactate and send it to the liver for recyling to glucose *even if there is enough oxygen available to not turn to glycolysis* (and with it lactate ptroduction).
=> Very quick production of lactate even at minimal exertion of our cells is observed more then a few times in ME research isn’t it? That may not be due to a lack of our mitochondria being able to produce enough ATP but more due to a lack of our mitochondria being able to recycle all important glutathione when our cells consume too few glucose. If the mitochondria don’t “want” to consume glucose / pyruvate, then the cytostol or cell core (the liquid where the mitochondria “swim” in) might have to increase glucose consumption *even if there is enough oxygen available*. Just in order to have enough carbs going through the improtant (glutathione recycling) pentose phosphate pathway.
Now the last twist comes:
But… …blocking of PDH is still the problem isn’t it? All that excessive ROS thing I wrote about is just a bad consequence isn’t it? If PDH was just fine then all would be nice and dandy wouldn’t we?
Well, as usual things are a bit more complicated then that. In one of the papers linked in the “hard science” parts I wrote yesterday, it is clearly said that the glutathione system can alter PDH’s working (a lot).
With “the glutathione system” we mean how much reduced glutathione is available, how much oxidized glutathione is available and how high or low is the ratio between reduced and oxidized glutathione?
Well, more then a few researches pointed to all three of them being altered in ME. And the linked research says it clearly: glutathionylation of PDH alters the working of PDH. In more plain speak: PDH and glutathion (either reduced or oxidized, a bit harder to find out which one of them) chemically bind to form a new molecule that doesn’t work as well (or at all?) as pure unmodified PDH for converting pyruvate to acetyl-CoA.
Simply said: the state of the glutathione system can increase or decrease the functioning of PDH a lot.
What decreases PDH functioning (too much reduced or too much oxidized glutathione) is a bit harder to find out with a partial brain fog but so far I’d say it is quite likely too much oxidized glutathione that inhibits it.
As the combo less reduced (reduced here meaning unoxidized) glutathione and more oxidized glutathione is the hallmark of chronic elevated oxidative stress I do find it far too soon to drop the notion that our cells might produce way too much oxidative stress.
As it seems that it is too much oxidized rather then too much reduced (“unoxidized”) glutathione that blocks PDH, it is possible to see a vicious circle here:
* PDH blocked? Less pyruvate consumption by the mitochondria.
* Less pyruvate consumption by the mitochondria? Less glucose being converted to pyruvate by the cytostol (“cell core liquid bath”).
* Less glucose being converted to pyruvate by the cytostol? Less usage of the pentose phosphate pathway.
* Less usage of the pentose phosphate pathway? A lot more oxidative stress and crippling the glutathione system.
* Crippling of the glutathione system? Further inhibition of PDH.
=> We have a potential vicious circle at our hands.
That alone likely isn’t enough to keep us that sick. Genetic weaknesses in PDH enzyme production could help increase the risk of getting trapped.
Also poor oxygen provision to the cells (ME peoples blood volumes and flow is reduced, RBC are stiff and are very unwilling to release their oxygen to the cells, breathing problems with many of us…) could be an important factor to keep this vicious circle going. Too poor oxygen provision increases ROS generation and that in turn can deplete the glutathione system.
Glycogen storage diseases could also come into play. People with poor ability to convert glucose and fructose to glycogen (a sort of storage for carbs) and convert glycogen back to glucose have a double challenge:
When they have a blood sugar spike after eating food, they can’t convert the excess to glycogen. Chances are high they will convert a lot of that excess to fat because too high blood sugar spikes are dangerous and need to be reduced urgently. Both converting carbs to glycogen and fat is a way to reduce that spike. If the conversion to glycogen is hampered, more fat is build. That makes fat more available to the cells even if you have a low fat diet.
When exerting however, a lack of any meaningful glycogen stores or the ability to quickly convert glycogen to glucose reduces the amount of carbs available to the cells.
If we combine both: less carbs and more fat available to the cells, then it’s easy to imagine that even a small skew towards inhibited PDH could be enough to get our mitochondria to consume way more ROS generating fatty acids.
=> So, when looking at many things, I still see the signature of an excessive ROS production in ME.
=> (epi-)Genetically crippled PDH can be part of it, but it doesn’t seem to explain things like changed complex-I and complex-II expression as seen by some research (The complex-I and II changes we experience seem to protect against excessive ROS production as I explained in the comments of a recent HR blog).
=> More then a few other (epi)-genetic weaknesses can get us more easy caught in such vicious circle too. Strong one time events like a strong infection can trigger us becomming trapped in it too, with chances higher the more genetic weaknesses we have surrounding this trap.
One thing I am a little surprised about with these findings which the findings from this latest paper seems fairly basic stuff to me, a non scientist and as Cort has stated others have suggested similar issues before.
Therefore I am rather surprised that Ron Davis’ team of super researchers haven’t come up with something similar by now?
This just doesn’t seem like rocket science to me.
One other thing I wanted to comment on was the glucose issue in ME/CFS. How my body handles or mishandles glucose was the first issue I became aware of around 22 years ago before I had full blown ME/CFS with it’s resultant lack of energy and inability to exercise much.
I found it impossible to regulate my blood sugar, it would drop like a stone so quickly after eating and I would have terrible symptoms like vertigo, dizziness, loss of balance to the extent of nearly falling over or off a chair. Changing my diet to a much lower carb diet helped a bit but glucose was still a problem.
Once it was obvious my adrenals were in such a bad way I needed long term steroids to replace the cortisol that they didn’t make, the situation with my bs improved but it is still an issue now. My blood sugar’s are higher in the day now and no longer drop like a stone but my brain still doesn’t like it when it gets to what should be a normal, lowish blood sugar level and gives me symptoms like sweating, headaches and mild dizziness so I know I need to eat something like natural peanut butter and a teaspoon of MCT oil plus a few peanuts to raise my bs a bit. Also when I walk my dog my blood sugar drops within 12 minutes and the sweating can start and the lactate builds up in my leg muscles so I can only walk for another 8 minutes or so.
So for me it is of no surprise that the way our body handles glucose is an important issue in ME/CFS.
I think I did found a clear picture on how the fuel mix (carbs versus fatty acids) affects ROS levels.
The research linked here is for the mitochondria of beta-cells. That are pancreas cells. I don’t know if those were healthy or not, but I do think they were healthy. Chances they researched ME patient cells are rather low 😉 or 🙁 due to lack of research?
It’s the right hand figure 4C in https://www.researchgate.net/figure/Effect-of-chronic-elevated-glucose-and-palmitate-on-ss-cell-mitochondrial-membrane_fig4_44575536. It possibly uses a different metric to measure ROS generation then Cara Tomas and her group did, but the hight of the bars are pretty self-explanatory IMO:
For feeding the cells with 5mM of glucose only, the ROS cell positive bar is less then 0.5%.
For feeding the cells with 20mM of only glucose, the ROS cell positive bar is roughly (reading on sight) 1.5%.
For feeding the cells with 5mM of glucose and 0.3mM of palmitate (fatty acid) the ROS cell positive bar is roughly 5%.
For feeding the cells with 20mM of glucose and 0.3mM of palmitate the ROS cell positive bar is roughly 7%.
These likely don’t translate into straight 10+ fold increases in ROS production when changing the fuel from 5mM of glucose to 5mM of glucose plus 0.3 mM of palmitate (fatty acid). The reason is because this technique IMO doesn’t measure exact amounts of ROS bu rather “ROS fluorecent cells” or something like that. Still, it represents and obvious increase in ROS production.
=> (likely) “low-ish” amounts of glucose plus a dose of fatty acids increases the amount of “ROS positive cells” a lot more then feeding the same cells a (likely rather excessive and inflammatory) dose of 20mM of glucose without adding fatty acids to it.
=> It therefore stems to reason that fatty acid availability has a very strong influence on ROS production.
=> I see good reason why it is not primairly fatty acid in the food substrate but actual fatty acid consumption of the cells that increases ROS production so much.
=> If so, and if our cells (mitochondria) turn to quite a bit higher fatty acid consumptiom paired with reduced glucose consumption due to PDH inhibition, then I can almost do nothing else then conclude we have excessive strong ROS production in our cells for equal amounts of ATP output compared to healthy people. That is when feeding the cells “real life fuel / blood” containing both glucose and fat(ty acids).
=> The “excessive ROS plays a key role in ME idea” may be very much alive rather then close to the brinck of death! In depth research with ME versus healthy cells with these sort of “fuel mixes” might be a key thing to do. And there clearly exist techniques to do so.
I am currently building a battery test for supporting my revision of my ME/SCF pension. So far I have done an effort test of two consecutive days and my results I think are in line with what this study says:
1-Functional capacity:
During the Re-test, a decrease in the Anaerobic Threshold of 7% and of the work power in 5% is observed, which describes the PEMS (Post-exertional malaise), which goes from 79% in the first test to 72% in the re-test.
2-Assessment of the Autonomic Nervous System:
Existing dystermia, both at basal level and during the effort, are manifesting an alteration in peripheral vascular perfusion that prevents it from adapting to change Alteration in the relationship between the Central and Peripheral Temperature with the Central being more than 2 to 3 degrees above the Peripheral Temperature.
The peripheral temperature allows for vascularization, and in his case, it does not do it automatically and therefore muscle inflammation occurs. This not only happens with physical exercise, but it can also happen with meal digestions that become longer, or while working and thinking because you need to vascularize the brain. When peripheral circulation is not activated, you become fatigued and inflammation occurs. The more stimuli you have, the greater the fatigue, and the mental activity also cause fatigue.
3-Lactic Acid metabolism:
During both tests, maximum lactate parameters are reached that meet maximum test criteria, during recovery, no lactate clearance is observed in the first minutes of recovery, which are objectifying a lack of post-effort recovery that causes subsequent inflammation.
4-Metabolic Inflexibility during exercise:
There is a limitation to metabolize fat as an energy substrate at the mitochondrial level, with a very highly glucose-dependent metabolism to be able to perform any activity without generating fatigue. In the re-test, when fatigue is established, a worsening in the energy efficiency of fats was observed (an indirect measure of assessment of mitochondrial function).
My question is…Is there a Laboratory Test that I can run to see whether I obtain similar results mentioned in this research study, or that is only available in the context of a Research Study and can not be ordered in a regular lab?
Thanks in advance!
Hi Carlitos,
is it too private to ask where your test was done?
it seems like they are very knowledgeable.
if too personal question, my apology in advance, and wish you return to full health.
Hey Cort thanks for this always greatly appreciate your work. Any updates on the Cortene drug trials which I thought seemed really promising?
PDH is significantly affected in influenza infection, we need to look closely at the effect of other viruses on this enzyme system. The shut down is temporary in most people but in pwme and many with FM it may be a prolonged interference. In particular, at the moment Covid-19 coronavirus infection is causing energy problems resembling ME. Maybe the coronaviruses cause this effect on these enzymes.
This study looked effects of influenza infection on MDCK cells. Anyone know of other studies implicating PDH in viral infection?
Effect of influenza virus infection on key metabolic enzyme activities in MDCK cells
Robert Janke, Yvonne Genzel, Maria Wetzel & Udo Reichl
BMC Proceedings volume 5, Article number: P129 (2011)
Thanks Ian for the clue!
Rather then looking for other virusses I thought I’d look into sepsis. That is both far enough from a specific virus yet strongly related to infection, inflammation and excessive oxidative stress. The goal was to see if decreased PDH activity is sort of a general response to those.
Bingo: Looking up the combination “pyruvate dehydrogenase and sepsis” give a rich treasure cache.
Examples:
https://pubmed.ncbi.nlm.nih.gov/3521310/
The summary is a bit confusing and poorly worded but if I get it right: chronic sepsis does not alter PDH except increases its activity in liver. Sepsis as in likely quick onset (very) sepsis significantly decreases PDH activity.
“Sepsis (either small or large septic abscess) resulted in threefold decrease in the concentration of active complex relative to control or sterile inflammatory animals.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471046/
Sepsis gives PDH a big hit, up to three fold less as seen in the graphs. It slowly starts to recover after 72 hours of initial onset. Sort of pointing again to it being (in sepsis) mainly an accute but very strong effect.
Note: the “PDH dip and recovery curve” seems somewhat similar to how PEM and its recovery feels to me.
https://www.atsjournals.org/doi/full/10.1513/AnnalsATS.201505-267BC
The graphs show badly reduced PDH quantity and activity after sudden onset sepsis. PDH activity REDUCES by as much as FOUR times on average and even FIVE times as much in median value (leaving even worse drops for “the vulnerables” being probably us) 48 hours after sepsis onset.
=> Have we hear a potential clear explanation of the “ME sudden (viral / pathogenic) onset” phenomen??? If so, that’d be huge!
Wow! dejurgen, thanks for your sleuthing and insights
The above were just the first three hits that popped up. I thought about combining “pyruvate dehydrogenase borrelia” but that didn’t delivered results. Then I turned to “pyruvate dehydrogenase epstein barr”
Bingo again:
https://forums.phoenixrising.me/threads/enhanced-aerobic-glycolysis-by-epstein-barr-virus-latent-membrane-protein-1.58953/
A 2018 forum topic by someone called “nanonug” linking following research https://pubmed.ncbi.nlm.nih.gov/28827059/
“Latent membrane protein 1 (LMP1) is a principal viral oncoprotein in Epstein-Barr virus (EBV)-associated malignancies… …In the presence of oxygen, we demonstrated that glucose consumption, lactate production and lactate dehydrogenase (LDH) activity were significantly increased upon LMP1 expression in NPC cells and in a LMP1 variant derived from NPC patients-transformed BALB/c-3T3 cells. The amounts of the α subunit of hypoxia-inducible factor-1 (HIF-1α), a key regulator of aerobic glycolysis, and its targets, pyruvate dehydrogenase kinase 1 (PDK1) and the pyruvate kinase M2 (PKM2) isoform, were also consistently elevated by LMP1. Moreover, in parallel with reductions in the oxygen consumption rate and mitochondrial membrane potential in cells, an augmented extracellular lactate concentration was observed due to LMP1 induction.”
=> In plain text: Something called “latent membrane protein”, likely working for a long time after initial EBV infection judging by its name, does a whole lot of things associated with PDH being crippled:
More lactate production, reduced oxygen consumption and reduced mitochondrial membrane potential (related to how “fit” mitochondria are).
Part of the body chemicals this LMP1 increases is hypoxia-inducible factor-1 (HIF-1α), that is a key chemical for (starting to mount) protecting cells during hypoxia. That seems to increase pyruvate dehydrogenase kinase, a chemical removing part of the pyruvate dehydrogenase.
That sort of makes sense as (HIF-1α) is high if oxygen is too low, and reducing pyruvate dehydrogenase shifts energy production more away from oxygen using mitochondrial production towards anaerobic glycolysis. That is a good thing to do in *temporary* hypoxia.
=> EBV seems (able to) to create a constant lasting decrease in pyruvate dehydrogenase activity.
=> Both prior (likely at adult age) EBV and a single strong infection seem able to create a strong to very strong hit on PDH activity. If the combo is too strong (or other epi-genetic weaknesses exist) that may disrupt energy product throughout the body vastly. Better said: such combo would really hamer PDH activities badly for days if not weeks at end.
deJurgen, i think you like this one from Dr. Pall
https://me-pedia.org/wiki/Nitric_oxide_hypothesis
Dejurgen, does all this mean, then, that the impaired PDH/pyruvate is due to infections, and prolonged/chronic inflammation?
And, that it is just a symptom of the underlying cause(s)?
Really appreciate the answer, to be sure I understand it! Major brain and focus issues. Thank you!
Hi,
can someone explane what a short chain acyl COA dehydrogenase deficiency means for mitochondria funktion?
Thanks
Re ME/CFS : lactate dehydrogenase etc. are activated by exogenous NaHS treatment.
This indicates that some subtypes of ME/CFS may be H2S deficiency diseases.
Some other types of ME/CFS like diseases may however be H2S excess conditions as originally postulated by Lemle.
The ability of major enviromental toxins to inhibit major H2S biosynthesis enzymes could be part of the etiology of ME/CFS.
I have put a big survey on scribd at 487511969
For how H2S stimulates the tricarboxylic acid cycle see M Liang et al. PMID 25524832. The slow release of H2S from NaHS improves glucose metabolism in cardiomyocytes. Exogenous NaHS treatment was reported to increase glucose uptake, the efficiency of glycolysis and the citric acid cycle; the key enzymes including lactate dehydrogenase, pyruvate kinase and succinate dehydrogenase were apparently activated by H2S. [This could have been by sulfhydration where H2S is inserted into cysteine residues] The speeding up of tricarboxylic acid cycle may be a normal healthy cell situation. PMID 33137711 gives a more general picture of H2S led mitochondrial control . Another paper of interest for H2S control of glucose homeostasis is PMID 28699407; here both pro and anti effects are mentioned for adipocytes and skeletal muscles cells).
H2S exists in equilibrium with poly-sulfides which act as stores. Oligo-sulfides are thought to be much more biologically active than the monomer. Can get very long chains at least in vitro. These are likely,if formed in vivo, to be very inactive, removing the sulfane sulfurs from circulation. These long chain sulfanes form with rubber vulcanization using e.g. benozthiazole based accelerators which get into the environment in large amounts via rubber tire tread wear nano-particles which may act upon ingestion as H2S enzyme inhibitors and poly-sulfide deactivators. This is a possible trigger of ME/CFS.
I studied poly-sulfides and poly-selenides in an industrial laboratory long before the current awareness that such poly-sulfides are major biochemical hitters.
Later on I discussed the above ideas in an academic research laboratory where I studied. The lab boss fell ill with ME/CFS. He seems to like my scribd survey mentioned. This need re-writing.
To all who contribute to the comments section – Thanks you so very much. I wish I could mentally process what is being said, I’m sure I would have something to contribute. I often just cant read stuff.
I have a degree in Physiology, got sick with ME half way through it, 37 years ago. My job now is to keep going, keep my spirits up, pat the dog and hope that I can glean bits in the articles from time to time. As I dont go anywhere much, I am able to donate to HR. If you can, please donate. Best to everyone. Linda