Pyruvate dehydrogenase deficiency does not lead to fatigue: Fluge & Mella's PDH impairment revisited

Hip

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Fluge and Mella Found a Pyruvate Dehydrogenase Impairment in ME/CFS: Does This Really Explain ME/CFS?

A new argument suggests pyruvate dehydrogenase (PDH) impairment may not be a candidate for the underlying cause of ME/CFS.



In Fluge and Mella's 2016 metabolomic study, they found impaired pyruvate dehydrogenase function in ME/CFS, and it has been speculated this might be the cause of the apparent energy metabolism dysfunction of this disease — a dysfunction which causes fatigue and other ME/CFS symptoms.

@Kalliope posted a link to a pertinent argument raised by Dr Yngve Thomas Bliksrud in the Journal of the Norwegian Medical Association (Google translation here), in which Dr Bliksrud discusses Fluge and Mella's results, and points out that:
Chronic fatigue is not a typical symptom in patients with primary genetic pyruvate dehydrogenase deficiency, neither severe nor mild
Dr Bliksrud says the fact that patients with genetic PDH deficiency diseases do not generally experience fatigue suggests that the PDH impairment found by Fluge and Mella may not be the cause of ME/CFS.

But conceivably Fluge and Mella's PDH impairment may be a consequence of some other more fundamental energy metabolism dysfunction in ME/CFS, rather than the actual cause of the ME/CFS energy dysfunction.

So what might be the real underlying energy metabolism dysfunction that both causes ME/CFS, and gives rise to this PDH impairment?


One possibility is comes from the 2009 energy metabolism studies of Myhill, Booth and McLaren-Howard where they found that the mitochondrial translocator protein is blocked in ME/CFS, and posited this causes an energy metabolism blockage. (Note though that translocator protein blockage was not the only energy metabolism impairment found by Myhill et al in ME/CFS).

Myhill, Booth and McLaren-Howard point out that if the translocator protein is blocked, then pyruvate dehydrogenase automatically becomes inhibited. See their 2012 study:
If TL [translocator protein] is not working properly, oxidative phosphorylation will be inhibited, pyruvate dehydrogenase becomes inhibited and also the Krebs cycle
So it's possible that the PDH inhibition found by Fluge and Mella may be a consequence of the translocator protein blockage found by Myhill, Booth and McLaren-Howard in ME/CFS patients. Or may be a consequence of some other as yet undiscovered energy metabolism dysfunction.

Note that Myhill et al use the term "translocator protein" to refer to the adenine nucleotide translocator (ANT).


Also of relevance: Enterovirus-Induced ANT Autoantibodies: the Cause of ME/CFS? Could autoantibodies that target ANT (the mitochondria translocator protein) be the cause of ME/CFS? Such ANT autoantibodies would certain fit in with Fluge and Mella's finding that there is "something in the serum" of ME/CFS patients that is causing the energy metabolism blockage (autoantibodies are found in the blood serum).
 
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Hip

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One problem with this argument is that we don't actually have a deficiency according to current hypotheses. We have a suppression.
True, I guess if the PDH suppression Fluge and Mella found in ME/CFS patients created a much more severe impairment of PDH functioning than is found in PDH deficiency diseases, then possibly that might negate Dr Bliksrud's argument. But the fact that no fatigue appears even in severe PDH deficiency disease suggests that PDH impairment is not the answer we are looking for.
 
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Jesse2233

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From NIH on pyruvate dehydrogenase deficiency symptoms:
The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. People with pyruvate dehydrogenase deficiency usually have neurological problems as well. Most have delayed development of mental abilities and motor skills such as sitting and walking. Other neurological problems can include intellectual disability, seizures, weak muscle tone (hypotonia), poor coordination, and difficulty walking.
No mention of fatigue, but perhaps the age of onset determines symptoms.
 
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diseases of pyruvate dehydrogenase deficiency are indeed different and more severe in a lot of ways than CFS, often leading to death of infants from lactic acidosis. I do wonder if there are similarities. Do people with CFS tend to have higher lactic acid?
 

Hip

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Beyond targeting a chronic infection causing autoimmunity, or the resulting autoantibodies, is there a good way to boost function of the ANT translocator protein?
Not that I have come across.

If in ME/CFS the ANT protein is indeed being attacked by an ANT autoantibody, there may be ways to thwart this attack within the cell; this post details the four proposed ways in which the ANT autoantibody may cause dysfunction to the ANT protein in the cell. Maybe someone could figure out how to block that attack inside the cell.

But we don't know if ANT autoantibodies actually exist in ME/CFS (nobody has checked to see if they are present or not).

Dr John McLaren-Howard thinks that in ME/CFS the ANT protein is being blocked by exogenous or endogenous toxins or chemicals, and his lab (Acumen Lab) provides a test to detect which chemicals are present and attached to the ANT protein. I don't find this idea convincing though, as we know that ME/CFS is usually triggered by viral infection, not toxic exposure.
 
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Hip

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Do people with CFS tend to have higher lactic acid?
ME/CFS patients may produce more lactate than healthy controls during physical exercise, and conceivably this may contribute to PEM. Very severe ME/CFS patient Dr Mark Vink published a study on exercise-induced lactate, with himself as the single subject.
 
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Learner1

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I don't find this idea convincing though, as we know that ME/CFS is usually triggered by viral infection, not toxic exposure.
Trigger vs. contribute to...

Everyone is toxic. Toxins can sit in the mitochondria and impair the function of the mitochondrial membrane, reducing ATP production. This was shared by researchers at the United Mitochondrial Disease Foundstion Conference I attended. And Myhill discusses them, and as you point out, there's the Acumen test which identifies toxins which are DNA adducts.

With the number of people reporting unfortunate side effects of methylation supplements around here, as well as those who know they're toxic and are trying to chelate/detoxify using various methods, its an area that deserves more attention.

I recently attended a series of lectures by Dr. Joseph Pizzorno who shared statistics on various toxins from various countries around the world as well as relationships between toxins and disease - we live in a toxic world, and some of us are the proverbial "canaries in the coal mine" and more susceptible to ill effects, especially if our bodies are challenged by other factors, like infections.

Though an infection may be a trigger, our underlying genetics, environmental exposures and biochemical status may impact the development or maintenance of this disease state.
 
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Hip

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Everyone is toxic.
Specific chemicals have been shown in studies to increase the risk of developing specific diseases; but saying that "everyone is toxic" does not really mean anything, and certainly does not address the question of which toxins are linked to which diseases.

If you think that a certain toxin or chemical increases the risk of developing ME/CFS, then as a scientist you need to go and do the hard work to prove that connection; otherwise there's no evidence to support your assertion.
 

Learner1

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Specific chemicals have been shown in studies to increase the risk of developing specific diseases; but saying that "everyone is toxic" does not really mean anything, and certainly does not address the question of which toxins are linked to which diseases.

If you think that a certain toxin or chemical increases the risk of developing ME/CFS, then as a scientist you need to go and do the hard work to prove that connection; otherwise there's no evidence to support your assertion.
No one said one certain toxin will flip you into ME/CFS. Many toxins can impact biochemistry and physiology, causing fatigue, which may contribute to the development of ME/CFS.

As just one example, scientists have done the hard work to find that the #1 worst toxin, arsenic, directly impacts mitochondria, reducing mitochondrial membrane potential, damaging mtDNA, and affecting neurological, renal, and cardiovascular function, which all contribute to fatigue. See attached...

Note that I didn't say that toxins were the cause in isolation. But arsenic can be a factor contributing to someone's ME/CFS. (It was for me...)

A myriad of other toxins can contribute to fatigue by impacting mitochondria, biochemistry and physiological functioning.

Like mold, for instance. Scientists gavecdone s lot of research on it, too. You just have to be willing to look for it.

Best to be wary, reduce toxic inputs and encourage toxins to leave the body. At least that was what was discussed at the toxin lecture I went to this evening by a researcher who's done a lot of work with toxins and detoxification protocols...
 

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echobravo

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I would definitely be interested in the link between mitochondrial membrane (dys)function and how it relates to different kind if toxins that might build up inside cells. Are there, for instance, any ME recovery or remission stories from people that went through detox regimes? What are typical toxins found by the Acumen test for ppl with ME, and what can be done to “remove” them from mitochondria? Is the Acumen test avail for ppl from abroad?

Also, what is the exact function of the translocator protein? Does it have co-factors? Is it affected by (under control of) the ANS in anyway through neurotransmitters or hormones? I ask this since the 2014 Japanese study found neuroinflammation in hypothalamus++ in the brain through PET scans.

@Learner1 you mentioned toxicity and methylation supplements, could you please elaborate on that? I get very ill if I try to supplement 5-MTHF, but do you see a connection with mitochondrial (or cell) toxicity related to such supps?
 

dannybex

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I don't find this idea convincing though, as we know that ME/CFS is usually triggered by viral infection, not toxic exposure.
IMO, I would say ME/CFS is hypothesized to be triggered by a viral infection. It's probably virtually impossible to know if ME/CFS isn't/wasn't triggered by a combination of things, with perhaps a viral (or other) infection being the most obvious, but not necessarily the 'lone' trigger or cause.
 

TreePerson

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So it has been found that translocator proteins are blocked but it has also been found that ME CFS cells begin working again when they are given the serum from healthy people?

This must mean therefore that the translocator proteins can unblock pretty easily? Or that they are only partially blocked so that giving healthy blood which does not have suppressed pyruvate is enough of a boost to give an impression of things working normally?

Due to the conflicting results of studies I have found myself wondering whether the problem is both inside and outside of mitochondria. So in the cells and in the serum.
 
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alex3619

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The issue with PDH suppression and lactic acidosis is that we do not really hear about this in ME. Yet its probably a mistake to think we have continuous PDH suppression, or at least the effects of it. There was some work, I think from the UK, showing we are alkaline at rest. Its post exertion that we head into prolonged acid states and are at risk of lactic acidosis. In lactic acidosis its a prolonged pH shift that alters body chemistry that sets up a feedback loop that worsens lactic acid status (via alteration of enzymes in red blood cells). It takes several days. Lactic acidosis, if it occurs in ME, would occur in patients who push themselves to over-exert for days, or are compelled to in forced rehab.

If suppression is occurring then lactic acid is a consequence of driving metabolic demand beyond aerobic capacity. I wonder if there have been deaths in very severe ME patients from this that have been ignored. For the rest of us I think its unlikely that lactic acidosis is a substantive risk.
 

bertiedog

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I don't find this idea convincing though, as we know that ME/CFS is usually triggered by viral infection, not toxic exposure.
In the first ATP study I had done, Dr McClaren Howard said the PARTIAL blockage I had was "probably viral". He couldn't tell me more than that. I think this was done around 2005 or 2007. I did have another ATP test done in 2009 and this time NICKEL was the cause of the partial blockage, no mention this time of a viral issue.

Nickel has showed up as a problem for me in other tests too. He said that nickel was occupying the site where manganese should be and that it would be unable to do the job that manganese did so I again ended up with low ATP. I think I know why I have this issue with nickel and have also had high mercury problems, the reason being I don't posses the enzyme GSTM1 that is responsible for the detoxification of heavy metals.

Pam
 

bertiedog

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f you think that a certain toxin or chemical increases the risk of developing ME/CFS, then as a scientist you need to go and do the hard work to prove that connection; otherwise there's no evidence to support your assertion
Isn't that exactly what Dr Myhill et all have done in their 3 published studies? I don't understand why more researchers haven't followed up on this toxic connection?

Pam
 

Hip

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A myriad of other toxins can contribute to fatigue by impacting mitochondria, biochemistry and physiological functioning.
A "myriad" of toxins can contribute to fatigue? Again that's just too vague. It's just alluding to the popular but non-specific notion that "toxins are bad". Which toxins contribute to fatigue, and where's the evidence that they can do so?

Broad generalizations will not really help get to cause of ME/CFS. That's not to deny that some people might have high levels of certain toxins in their body that may impact their health, but it's an unsubstantiated leap to assume that "toxins cause ME/CFS".

To my knowledge, the risk of developing ME/CFS has been linked to certain pesticides, and anecdotally to biotoxins like mold toxins, and Dr Goldstein thought tung oil might be a factor, but that's about it.



As just one example, scientists have done the hard work to find that the #1 worst toxin, arsenic, directly impacts mitochondria, reducing mitochondrial membrane potential, damaging mtDNA, and affecting neurological, renal, and cardiovascular function, which all contribute to fatigue.
Even if arsenic were to contribute to fatigue, than in no way implies it is a causal factor in ME/CFS.

Prior to getting ME/CFS, I suffered from a chronic recurrent urinary tract infection, and during every flareup I would feel significant fatigue for several days, as is common in UTIs. When I later developed ME/CFS after a viral infection, this same UTI fatigue when it occurred during a flareup would compound my ME/CFS fatigue. But that does not mean that UTIs cause ME/CFS or are even related to ME/CFS.


I would actually like try arsenic as a treatment for ME/CFS, since it has potent antiviral effects against coxsackievirus B, a virus I have high titers to. Ref: 1 But since arsenic accumulates in the body, and increases cancer risk, you would need to make a balanced decision. Arsenic was able to cure two cases of human ME/CFS apparently caused by Staphylococcus bacteremia. Ref: 1



In the first ATP study I had done, Dr McClaren Howard said the PARTIAL blockage I had was "probably viral". He couldn't tell me more than that. I think this was done around 2005 or 2007. I did have another ATP test done in 2009 and this time NICKEL was the cause of the partial blockage, no mention this time of a viral issue.
Everyone I have seen who was tested by Acumen Labs for chemicals on their translocator protein (ANT protein) has different chemicals, and in your case, you had different chemicals at different times. I don't think these chemicals are related to the actual cause of ME/CFS; you tend to find that specific chemicals are linked to specific diseases; but here the suggestion from Acumen is any chemical can cause ME/CFS. That does not ring true to me.
 
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