Metabolomic Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

[Consul]

I would think that it is indeed relevant for neurons in the brain. Yes, neurons don't utilize lipids for energy as much as other cells do. But neurons do engage in a lot of lipid metabolism for non-energy reasons, especially in order to maintain their dynamic membrane components, which are essential for the specific functions of neurons.

True. From the quote below i thought they put the whole blame for mecfs on the crosstalk in particular but they dont actually do that.

We posit that this crosstalk between mitochondria and peroxisomes plays an important role in maintaining energy homeostasis, and that dysregulation contributes to the fatigue and cognitive dysfunction that are hallmarks of ME/CFS

 

[Pyrrhus]

True. From the quote below i thought they put the whole blame for mecfs on the crosstalk in particular but they dont actually do that.

Yeah, it's clear that they did a big study and collected a lot of metabolomic data.

Then, they said "what does this all mean?"

The first draft of their article pointed out the significantly decreased levels of membrane phospholipids and initially put the "blame" on the Tri-Carboxylic Acid (TCA) cycle and on the Kennedy Pathway. (The TCA cycle is also known as the Citric Acid cycle and the Kennedy Pathway is also known as the CDP-choline pathway.)

The next version of their article put the "blame" on Peroxisome dysfunction and on the Kennedy Pathway.

Now, the final version of their article puts the "blame" on Peroxisome dysfunction.

To me, the main point of this study is simply the finding of significantly decreased levels of membrane phospholipids. That is a significant finding regardless of the explanation. These decreased levels of membrane phospholipids could be caused by many things, such as a simple depletion of a specific nutrient due to chronic inflammation...

 

[Consul]

https://www.healthrising.org/blog/2022/08/21/lipkin-chronic-fatigue-syndrome-puzzle/

Interresting comment from Herbert Renz Polster in the comment section here making the case for glial failure.

 

[mitoMAN]

Now, the final version of their article puts the "blame" on Peroxisome dysfunction.

.

Did you ever research PPAR (peroxisome proliferator-activated receptors ) ligands such as Bocidelpar which is trialed for ME/CFS by Systrom which are able to create new Peroxisomes, hopefully non dysfunctional ones?

 

[Methyl90]

In the metabolic improvement community, PUFAs are seen as the "evil" as regards their inhibitory action on glucose metabolism and damage to cell membranes ... but from what I read PUFAs are the only fats with agonist action on PPAR ligands. (there are three, each with specific target organs).

Furthermore, again based on the literature, they inhibit the GSK3B gene, similarly to Lithium.

Personally, using only extra virgin olive oil and eliminating saturated fats I have small inexplicable remissions on a small part of the symptoms ... I don't know if this is related.

Initially I followed the theories of Ray Peat strong advocate of saturated fat and the abolition of PUFA ... now not anymore.

Do you benefit from consuming organ meats that are rich in phospholipids? liver, heart, brain? personally yes, but the elements within them are so vast that only a vitamin and / or mineral could create remission.

https://en.m.wikipedia.org/wiki/PPAR_agonist

Has anyone ever taken hydrogen peroxide in drops?

 

[Niklas]

I saw a mention of PEA. Is this relevant:

Palmitoylethanolamide (PEA, N-hexadecanoylethanolamide) is an endogenous compound belonging to the family of N-acylethanolamines. PEA has anti-inflammatory and analgesic properties and is very well tolerated in humans. In the present article, the basal pharmacology of PEA is reviewed. In terms of its pharmacokinetic properties, most work has been undertaken upon designing formulations for its absorption and upon characterising the enzymes involved in its metabolism, but little is known about its bioavailability, tissue distribution, and excretion pathways. PEA exerts most of its biological effects in the body secondary to the activation of peroxisome proliferator-activated receptor-α (PPAR-α), but PPAR-α-independent pathways involving other receptors (Transient Receptor Potential Vanilloid 1 (TRPV1), GPR55) have also been identified. Given the potential clinical utility of PEA, not least for the treatment of pain where there is a clear need for new well-tolerated drugs, we conclude that the gaps in our knowledge, in particular those relating to the pharmacokinetic properties of the compound, need to be filled.

https://pubmed.ncbi.nlm.nih.gov/33114698/

 

[Methyl90]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175772/#!po=4.09836

https://pubmed.ncbi.nlm.nih.gov/26386875/

Sorry I'm having problems with the chat, I wanted to ask what you think of the Mitolipin product that Haidut sells on Idealabs based on phosphatidylcholine but on a saturated basis, thanks.

https://raypeatforum.com/community/...d-saturated-phosphatidylcholine-pc-mix.10398/

@sb4 @Learner1

 

[sb4]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175772/#!po=4.09836

https://pubmed.ncbi.nlm.nih.gov/26386875/

Sorry I'm having problems with the chat, I wanted to ask what you think of the Mitolipin product that Haidut sells on Idealabs based on phosphatidylcholine but on a saturated basis, thanks.

https://raypeatforum.com/community/...d-saturated-phosphatidylcholine-pc-mix.10398/

@sb4 @Learner1

I didn't notice much when using it but then again I dont notice much with regular choline anymore besides headaches. When I first took aGPC years ago I felt much better for a period of a few hours, all my autonomic symptoms improved, could never get it to work again though

 

[Wishful]

With these sorts of theories, my response is: figure out some (relatively safe) chemicals that will theoretically affect the pathway--positive or negative--and have some PWME try them. If there's no response, dump that theory.

 

[marcjf]

It

I saw a mention of PEA. Is this relevant:

Palmitoylethanolamide (PEA, N-hexadecanoylethanolamide) is an endogenous compound belonging to the family of N-acylethanolamines. PEA has anti-inflammatory and analgesic properties and is very well tolerated in humans. In the present article, the basal pharmacology of PEA is reviewed. In terms of its pharmacokinetic properties, most work has been undertaken upon designing formulations for its absorption and upon characterising the enzymes involved in its metabolism, but little is known about its bioavailability, tissue distribution, and excretion pathways. PEA exerts most of its biological effects in the body secondary to the activation of peroxisome proliferator-activated receptor-α (PPAR-α), but PPAR-α-independent pathways involving other receptors (Transient Receptor Potential Vanilloid 1 (TRPV1), GPR55) have also been identified. Given the potential clinical utility of PEA, not least for the treatment of pain where there is a clear need for new well-tolerated drugs, we conclude that the gaps in our knowledge, in particular those relating to the pharmacokinetic properties of the compound, need to be filled.

https://pubmed.ncbi.nlm.nih.gov/33114698/

View attachment 49251

It is not the PPAR-α we should focus on, but rather PPAR-δ.

 

[Methyl90]

It


It is not the PPAR-α we should focus on, but rather PPAR-δ.

Have you ever used anything that strengthen membranes?

 

[Violeta]

"BCP also showed agonist action on peroxisome proliferated activated receptor subtypes, PPAR-α and PPAR-γ."

"These results indicate that the aroma compound, trans-caryophyllene, is PPAR-α agonist thus regulates cellular lipid metabolism in PPAR-α dependent manners."

"The activation of cannabinoid receptor 2 (CB2) has the beneficial effect of reducing neuroinflammatory response in the treatment of Alzheimer's disease (AD) and is suggested to trigger the peroxisome proliferator-activated receptor-γ (PPARγ) pathway; agonists of both receptors improve AD."

 

[Canyonk8]

can anyone dumb this thread down for me?

 

[Consul]

The plasmalogen levels in pwme looks like a big problem. These are supposed to protect the cell membrane from oxidative stress. Maybe the fatigue is just a warning that your cells are about to fall apart.

So there are probably two things that can cause this deficit, those are chronic inflammation and peroxysomal dysfunction which is the researchers theory. So how do you figure out which one is correct.

Im thinking it could very well be the chronic inflammation theory because the brainstem seems to be very implicated in mecfs, this is where the inflammatory reflex is operating from. If its dysfunctioning for some reasons like damage or presence of viruses then it might not be doing its job properly. Also many pwme have SFN which might inhibit many nerves that gives in/out signals to the brainstem. Also there is the lack of SCFA producers in the gut which is supposed to regulate our immune systems. (just to mention a few things)

edit: added some text

 

[Rufous McKinney]

Maybe the fatigue is just a warning that your cells are about to fall apart.

thats what today mostly feels like

 

[Methyl90]

Are you using PPAR agonist ?

 

[Alvin2]

Just saw this article posted up on the ME/CFS News twitter.

Anyone got the link to this Twitter?

 

[Consul]

Are you using PPAR agonist ?

Nope..

 

[Consul]

An interesting thing i learned (that i havent double checked) is that peroxysomes are named so because they use oxygen in their work which is to break down molecules for cleanup. Per oxy meaning presence of oxygen.

Also from what prior research has indicated we know there could be problems with the mitochondria in mecfs. At least some studies have suggested this.

So then it appears that both of the organelles that rely on oxygen in their work appears to be dysfunctional in mecfs. That could be a coincidence or it could be another hint that the main issue in mecfs is delivery of oxygen to the cells, hypoxia, pointing the finger at the vascular system.

 

[Consul]

Im also speculating that the reason Nitric Oxide Synthase is willfully downregulated by the body (Westermeister 2022) is because this pathway use molecular oxygen as well, so its the bodys attempt at saving the sparse oxygen for more important things. That could be detrimental to the blood vessels though since they should be dilating when proper to do so.