Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/CFS (Fluge et al., 2016)

[dannybex]

Also: there may be individual variations in metabolomic patterns.

IMO without a doubt.

 

[Marco]

Here's an interesting review on PDH complex impairment (most likely by ROS) in cerebral ischemia-reperfusion injury :

Pyruvate dehydrogenase complex in cerebral ischemia-reperfusion injury

http://www.braincirculation.org/art...=2;issue=2;spage=61;epage=66;aulast=Thibodeau

and some potential therapies!

 

[Snow Leopard]

I don't think you can predict in advance the symptoms that a mitochondrial translocator protein blockage might produce.

We already have some clues.

http://www.sciencedirect.com/science/article/pii/S0005272816300731
etc

Also:

The spectrum of pyruvate dehydrogenase complex deficiency: Clinical, biochemical and genetic features in 371 patients (severe and life threatening symptoms)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4003492/

 

[Hip]

We already have some clues.

There are also clues from chronic coxsackievirus B myocarditis / dilated cardiomyopathy patients, where there appears to be a virally-triggered autoantibody that partially blocks the mitochondrial adenine nucleotide translocator (ANT) protein, and causes an energy deficit in the heart muscle. The autoantibodies that target ANT have cross-reactivity to the VP capsid protein from coxsackievirus B.

Some details at the bottom of this earlier post.

It has been suggested that these heart diseases could be a model for ME/CFS.

That is to say, you could consider chronic viral myocarditis and its sequela dilated cardiomyopathy as a sort of "chronic fatigue syndrome of the heart," at least in terms of what's happening at the cellular level.

 

[Hip]

In terms of trying to bypass a defective pyruvate input into the mitochondria, in order to supply sources of energy to the mitochondria that ME/CFS patients can use, I found some interesting info on the use of dietary protein as an energy source.

If you look at the diagram below, some of the amino acids in protein route through the pyruvate entrance into the mitochondria, but other amino acids (like leucine and lysine), bypass the pyruvate route, and enter the mitochondria at the acetyl CoA or the acetoacetyl CoA input to the mitochondrial Krebs cycle.

This is very interesting for me, because I have often found that supplementing with a few grams of leucine will boost my energy levels a bit — and the fact that leucine can bypass the defective pyruvate input into the mitochondria in ME/CFS patients may explain why it gives me energy.

Using Amino Acids as Energy Sources

Amino acids that can be converted to pyruvate in order to enter the mitochondrial Krebs cycle are called glucogenic amino acids.

Amino acids that can be converted to acetoacetyl-CoA or acetyl-CoA in order to enter the mitochondrial Krebs cycle are called ketogenic amino acids.

➤ Amino acids that are exclusively glucogenic are:
alanine
arginine
asparagine
aspartic
cysteine
glutamic
glutamine
glycine
histidine
methionine
proline
serine
valine

➤ Amino acids that are both glucogenic and ketogenic are:
isoleucine
phenylalanine
threonine
tryptophan
tyrosine

➤ Amino acids that are exclusively ketogenic are:
leucine
lysine

Refs: Stage II of Protein Catabolism, Glucogenic amino acid - Wikipedia



For some reason though, I find that the energy-boosting effects of leucine disappear after 2 or 3 days of supplementation. I wonder if this is because some cofactors needed to convert leucine to acetyl-CoA get used up after a few days?

I am trying to find out what cofactors needed to convert leucine to acetyl-CoA.



If we can use amino acids like leucine to bypass our defective pyruvate mitochondrial input, it may help provide more energy for ME/CFS patients.

 

[nandixon]

For some reason though, I find that the energy-boosting effects of leucine disappear after 2 or 3 days of supplementation. I wonder if this is because some cofactors needed to convert leucine to acetyl-CoA get used up after a few days?

I am trying to find out what cofactors needed to convert leucine to acetyl-CoA.

Biotin is probably the most important limiting factor that can be supplemented, but perhaps your body may also just be returning to homeostasis.

 

[liverock]

We need adequate B vitamins as well to ensure citric acid and mitochondria function. I made the mistake of thinking we get adequate Vitamin B5 from our diet and it wasn't until I started taking a 250mg B5 on top of a low dose B complex that my energy level increased.

Chem Biol Interact. 2006 Oct 27;163(1-2):94-112. Epub 2006 May 1.
Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism.
Depeint F1, Bruce WR, Shangari N, Mehta R, O'Brien PJ.
Author information

Abstract
The B vitamins are water-soluble vitamins required as coenzymes for enzymes essential for cell function. This review focuses on their essential role in maintaining mitochondrial function and on how mitochondria are compromised by a deficiency of any B vitamin. Thiamin (B1) is essential for the oxidative decarboxylation of the multienzyme branched-chain ketoacid dehydrogenase complexes of the citric acid cycle. Riboflavin (B2) is required for the flavoenzymes of the respiratory chain, while NADH is synthesized from niacin (B3) and is required to supply protons for oxidative phosphorylation. Pantothenic acid (B5) is required for coenzyme A formation and is also essential for alpha-ketoglutarate and pyruvate dehydrogenase complexes as well as fatty acid oxidation. Biotin (B7) is the coenzyme of decarboxylases required for gluconeogenesis and fatty acid oxidation. Pyridoxal (B6), folate and cobalamin (B12) properties are reviewed elsewhere in this issue. The experimental animal and clinical evidence that vitamin B therapy alleviates B deficiency symptoms and prevents mitochondrial toxicity is also reviewed. The effectiveness of B vitamins as antioxidants preventing oxidative stress toxicity is also reviewed.

PMID:16765926

The full copy is here:
https://www.researchgate.net/public...min_family_on_mitochondrial_energy_metabolism

This paper concentrates purely on the citric acid cycle and B vitamins:
http://www.academia.edu/7492280/The_Role_of_B_Vitamins_in_the_Citric_Acid_Cycle

 

[gregh286]

In terms of trying to bypass a defective pyruvate input into the mitochondria, in order to supply sources of energy to the mitochondria that ME/CFS patients can use, I found some very interesting info on the use of dietary protein as an energy source.

If you look at the diagram below, it appears that some of the amino acids in protein route through the pyruvate pathway into the mitochondria, but other amino acids (like leucine and lysine), bypass the pyruvate route, and enter the mitochondria at the acetyl CoA or the acetoacetyl CoA input to the mitochondrial Krebs cycle.

This is very interesting for me, because I have often found that supplementing with a few grams of leucine will boost my energy levels a bit — and the fact that leucine can bypass the defective pyruvate input into the mitochondria in ME/CFS patients may explain why it gives me energy.

Using Amino Acids as Energy Sources
View attachment 18949​

The amino acids that route through the pyruvate input to the mitochondria are called glucogenic amino acids. Whereas the amino acids converted to acetoacetyl-CoA or acetyl-CoA are called ketogenic amino acids.

Ref: Stage II of Protein Catabolism



For some reason though, I find that the energy-boosting effects of leucine disappear after 2 or 3 days of supplementation. I wonder if this is because some cofactors needed to convert leucine to acetyl-CoA get used up after a few days?

I am trying to find out what cofactors needed to convert leucine to acetyl-CoA.



If we can use amino acids like leucine to bypass our defective pyruvate mitochondrial input, it may help provide more energy for ME/CFS patients.

Hi hip.
I noticed major improvement on amino acids this year....made a thread on it.
Why not take a broad based amino as opposed.to specific targeting ? Any particular reason?

 

[gregh286]

Biotin is probably the most important limiting factor that can be supplemented, but perhaps your body may also just be returning to homeostasis.

Is this why ron davies found an "unbelievable biotin deficiency in whitney?" As he used up all his biotin as a amino acid cofactor ? Am I grasping this correctly.

 

[eljefe19]

Hi hip.
I noticed major improvement on amino acids this year....made a thread on it.
Why not take a broad based amino as opposed.to specific targeting ? Any particular reason?

Which amino product do you take?

 

[gregh286]

Which amino product do you take?

I started in March on aakg. I deteriorated so I switched to PhD brand protein powder. Been mint ever since. I can still crash but nowhere near as often.
Check thread "complete symptom relief on No2 black"

 

[rosie26]

Could someone do a new thread with a list of things that could help when it is sorted. I can't read all this thread, it's too much reading for me. If possible, many thanks.

 

[NexusOwl]

Could someone do a new thread with a list of things that could help when it is sorted. I can't read all this thread, it's too much reading for me. If possible, many thanks.

I started this: http://forums.phoenixrising.me/inde...carbohydrates-diet-based-on-faulty-pdh.48491/

I would love if some of you came to discuss

 

[leokitten]

Apologies if I missed discussion of this somewhere, what about the fatty acid (from lipids) metabolic pathway? If I'm not mistaken this is done without the PDC (and thus PDH) to generate acetyl-CoA?

If there is significant inhibition of glucose metabolism and observed compensatory increase in amino acid metabolism, wouldn't they also observe significant up regulation of fatty acid metabolism in patients vs controls?

 

[eljefe19]

Apologies if I missed discussion of this somewhere, what about the fatty acid (from lipids) metabolic pathway? If I'm not mistaken this is done without the PDC (and thus PDH) to generate acetyl-CoA?

If there is significant inhibition of glucose metabolism and observed compensatory increase in amino acid metabolism, wouldn't they also observe significant up regulation of fatty acid metabolism in patients vs controls?

I believe, that in men the fatty acid metabolism was upregulated more so than aminos, which were found to be upregulated more in women. However, the brain fog is real tonight.

 

[eljefe19]

I started in March on aakg. I deteriorated so I switched to PhD brand protein powder. Been mint ever since. I can still crash but nowhere near as often.
Check thread "complete symptom relief on No2 black"

I was checking out Ph.D.'s products and they have many varieties. Which protein powder have you had specific success with?

 

[Hip]

Why not take a broad based amino as opposed.to specific targeting ? Any particular reason?

The reason is explained in my post. Fluge and Mella found in ME/CFS an impairment in the pyruvate input into mitochondria. Ketogenic amino acids like leucine and lysine, when used as a fuel for the mitochondria, are able to bypass the blocked pyruvate input, so should not be affected by the pyruvate defect.

So it makes sense to experiment with mitochondrial energy sources like leucine and lysine that do not rely on this pyruvate input.

However, note in normal circumstances, amino acids (from protein) only provide around 10% to 15% of our total energy, with the rest of the energy coming from carbohydrates and fats, so amino acids are only a relatively minor source of energy.

 

[eljefe19]

@Hip in the interest of Guinea pigging myself I think I'm going to buy Leucine powder and start supplementing it into my shakes. 10-20g at a time. Will report back. Is Lysine safe to take in high dosages as well?

 

[Hip]

@Hip in the interest of Guinea pigging myself I think I'm going to buy Leucine powder and start supplementing it into my shakes. 10-20g at a time. Will report back. Is Lysine safe to take in high dosages as well?

I have only taken 2 to 5 grams of leucine per day. Lysine makes me feel worse, even in doses of just 1 gram daily.

 

[eljefe19]

I have only taken 2 to 5 grams of leucine per day. Lysine makes me feel worse, even in doses of just 1 gram daily.

Hmm. Wonder why Lysine makes you worse. Maybe some kind of viral die off?
I will start with 10g of Leucine and report back.