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

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

Link is here.

Abstract:
Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. The pathogenesis is not fully understood. A syndrome clinically similar to ME/CFS has been reported following well-documented infections with the coronaviruses SARS-CoV and MERS-CoV. At least 10% of COVID-19 survivors develop post acute sequelae of SARS-CoV-2 infection (PASC). Although many individuals with PASC have evidence of structural organ damage, a subset have symptoms consistent with ME/CFS including fatigue, post exertional malaise, cognitive dysfunction, gastrointestinal disturbances, and postural orthostatic intolerance. These common features in ME/CFS and PASC suggest that insights into the pathogenesis of either may enrich our understanding of both syndromes, and could expedite the development of strategies for identifying those at risk and interventions that prevent or mitigate disease.

Methods

Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls.

Results

In ME/CFS cases, regression, Bayesian and enrichment analyses revealed evidence of peroxisomal dysfunction with decreased levels of plasmalogens. To the best of our knowledge, this is the first study suggesting peroxisomal dysfunction in ME/CFS based on a comprehensive plasma metabolomic analysis. Other findings included decreased levels of several membrane lipids, including phosphatidylcholines and sphingomyelins, that may indicate dysregulation of the cytidine-5'-diphosphocholine pathway. Enrichment analyses revealed decreased levels of choline, ceramides and carnitines, and increased levels of long chain triglycerides (TG) and hydroxy-eicosapentaenoic acid. Elevated levels of dicarboxylic acids were consistent with abnormalities in the tricarboxylic acid cycle. Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873).

Conclusion

Our findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight new abnormalities that may provide insights into the pathogenesis of ME/CFS.
Emphasis above is my own. It made me think of a relatively recent (6-8 months ago..?) discussion I saw regarding plasmalogens. I made preliminary notes on them but didn't search further - perhaps this is worth exploring? @Pyrrhus @Hip ?

Here are the notes I took:

Listened to an interesting discussion between Dr Seeds (somewhat scammy peptide doctor) and Dr Goodenowe (plasmalogen expert). He theorises that many issues in aging and chronic disease are present because of a lack of plasmalogens, and that returning to a healthy plasmalogen level can return the majority of function / help regenerative capacity dramatically.

Only starting to read about this as of this moment - preliminary info. Need to flesh out.

Plasmalogens are glycerophospholipids, more specifically plasmenyls with an ester linked lipid at the sn-2 carbon on the glycerol backbone. They fall into either plasmenylcholine (PC), or plasmenylethanolamine (PE, sometimes written plasmenylethalomine) plasmalogens, depending on their head group. They are found in cell membranes in immune, cardiac, and nerve cells, and are theorised to be intimately involved in the mediation of the effects of reactive oxygen species (ROS), as well as modulating cell membrane dynamics and serving as cellular signalling molecules.

Plasmalogens are synthesised in peroxisomes, small cytoplasmic organelles that in addition to plasmalogen production, are involved in the catabolism of long-chain fatty acids, branched-chain fatty acids, D-amino acids, polyamines, bile acid intermediates in liver tissue, and serve to reduce hydrogen peroxide.

A novel, orally available plasmalogen precursor, PPI-1040, was developed recently (by Dr Goodenowe’s team? Haven’t checked). It demonstrated dramatically positive effects in a mouse model of plasmalogen deficiency. Dr Goodenowe also spoke about multiple other studies in which their precursor was able to treat and prevent degenerative diseases - in some cases even returning to normal function despite ongoing treatment with a disease-inducing drug or intervention.
There didn't seem to be very much available pharmaceutically or in the news/literature, so I didn't look into it more at the time. If it is significant to ME/CFS then it is likely worth more effort.
 

Pyrrhus

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Thanks for posting!

This metabolomics preprint was originally written by the authors with a different title, and is discussed here:

Dysregulation of the Kennedy Pathway and Tricarboxylic Acid Cycle in ME/CFS (Che et al., 2021) (Pre-print)
https://forums.phoenixrising.me/thr...cle-in-me-cfs-che-et-al-2021-pre-print.84668/
This metabolomics paper found decreased levels of certain membrane phospholipids in ME patients compared to controls, notably phosphatidyl-choline, phosphatidyl-ethanolamine, and related plasmalogens. This confirms previous research findings of decreased membrane phospholipids.

Phosphatidyl-choline and phosphatidyl-ethanolamine are the two most abundant phospholipids in cells and are important components of cell membranes and mitochondrial membranes, especially in the nervous system.

The authors suggest that this finding might indicate metabolic changes to the Kennedy Pathway, also known as the CDP-choline pathway, which is one of two metabolic pathways for synthesizing phosphatidyl-choline in the body. The other pathway is the CDP-ethanolamine pathway, which synthesizes phosphatidyl-ethanolamine, and then converts it to phosphatidyl-choline with the use of a methyl donor (AdoMet/SAMe).

Whereas in the previous draft of this paper they suggested that these findings might indicate metabolic changes to the Tricarboxylic Acid Cycle (TCA), in this draft they suggest that these findings might indicate peroxisomal dysfunction.

To me, however, these findings simply suggest downstream deficiencies related to oxidative stress:
To me, the lack of certain phospholipids could come down to a simple secondary nutrient deficiency, as is often seen in the case of oxidative stress or chronic inflammation. As an example, oxidative stress might lead to a lack of methyl donors, which would disrupt the activity of Phosphatidyl-ethanolamine methyl-transferase (PEMT) in the liver, compromising the CDP-ethanolamine pathway to the eventual synthesis of phosphatidyl-choline. In this case, the observed lack of certain phospholipids would also be seen in other conditions with oxidative stress or chronic inflammation.

For more information on how oxidative stress can result in the downstream deficiencies seen in this study, see this discussion:

Neurochemical abnormalities in CFS: a pilot magnetic resonance spectroscopy study at 7 Tesla (Godlewska et al., 2021)
https://forums.phoenixrising.me/thr...-study-at-7-tesla-godlewska-et-al-2021.85779/


EDIT: Clarified that this paper is a new draft of a previously discussed draft of this paper.
 
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Thanks for posting!

This metabolomics study is a follow-up to a previous metabolomics study by the same authors:

Dysregulation of the Kennedy Pathway and Tricarboxylic Acid Cycle in ME/CFS (Che et al., 2021) (Pre-print)
https://forums.phoenixrising.me/thr...cle-in-me-cfs-che-et-al-2021-pre-print.84668/



Whereas in their previous metabolomics study they suggested that these findings might indicate metabolic changes to the Tricarboxylic Acid Cycle (TCA), in this study they suggest that these findings might indicate peroxisomal dysfunction.

To me, however, these findings simply suggest downstream deficiencies related to oxidative stress, as described in this discussion:

Neurochemical abnormalities in CFS: a pilot magnetic resonance spectroscopy study at 7 Tesla (Godlewska et al., 2021)
https://forums.phoenixrising.me/thr...-study-at-7-tesla-godlewska-et-al-2021.85779/
Very interesting, thank you
 

Pyrrhus

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This metabolomics study is a follow-up to a previous metabolomics study by the same authors:

Dysregulation of the Kennedy Pathway and Tricarboxylic Acid Cycle in ME/CFS (Che et al., 2021) (Pre-print)
Oops, I just realized that this is NOT a follow-up study, rather it is the exact SAME study.

Since this is a pre-print, not a published study, the authors are free to rewrite this paper as they see fit.

They have now re-written the pre-print with a different title and a different hypothesis.

Whereas in their previous draft of this paper they suggested that these findings might indicate metabolic changes to the Tricarboxylic Acid Cycle (TCA), in this draft they suggest that these findings might indicate peroxisomal dysfunction.