Dysregulation of the Kennedy Pathway and Tricarboxylic Acid Cycle in ME/CFS (Che et al., 2021) (Pre-print)
Authors: Xiaoyu Che, Christopher R. Brydges, Yuanzhi Yu, Adam Price, Shreyas Joshi, Ayan Roy, Bohyun Lee, Dinesh K. Barupal, Aaron Cheng, Dana March Palmer, Susan Levine, Daniel L. Peterson, Suzanne D. Vernon, Lucinda Bateman, Mady Hornig, Jose G. Montoya, Anthony L. Komaroff, Oliver Fiehn, W. Ian Lipkin
https://www.medrxiv.org/content/10.1101/2021.06.14.21258895v1.full
This is a (non-peer-reviewed) preprint from Ian Lipkin and a whole host of collaborators.
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).
The authors also suggest that their findings might indicate metabolic changes to the Tricarboxylic Acid Cycle (TCA), also known as the Citric Acid Cycle, which is the main energy-generating metabolic pathway in the cell.
The authors further suggest that the observed metabolite differences might serve as a biomarker for ME, especially in females.
Excerpt:
(spacing added for readability)
Authors: Xiaoyu Che, Christopher R. Brydges, Yuanzhi Yu, Adam Price, Shreyas Joshi, Ayan Roy, Bohyun Lee, Dinesh K. Barupal, Aaron Cheng, Dana March Palmer, Susan Levine, Daniel L. Peterson, Suzanne D. Vernon, Lucinda Bateman, Mady Hornig, Jose G. Montoya, Anthony L. Komaroff, Oliver Fiehn, W. Ian Lipkin
https://www.medrxiv.org/content/10.1101/2021.06.14.21258895v1.full
This is a (non-peer-reviewed) preprint from Ian Lipkin and a whole host of collaborators.
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).
The authors also suggest that their findings might indicate metabolic changes to the Tricarboxylic Acid Cycle (TCA), also known as the Citric Acid Cycle, which is the main energy-generating metabolic pathway in the cell.
The authors further suggest that the observed metabolite differences might serve as a biomarker for ME, especially in females.
Excerpt:
Che et al 2021 said:
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.
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.
In ME/CFS cases, the regression, Bayesian and enrichment analyses all revealed abnormal levels of several membrane lipids indicating dysregulation of the Kennedy pathway: decreased plasma levels of plasmalogens, phosphatidylcholines, phosphatidylethanolamines, sphingomyelins, and phospholipid ethers. Enrichment analyses revealed decreased levels of cholines, ceramides and carnitines, and increased levels of long chain triglycerides, dicarboxylic acids, hydroxy-eicosapentaenoic acid, and the tricarboxylic acid cycle intermediates alpha-ketoglutarate and succinate.
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). Our findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight specific abnormalities that may provide insights into the pathogenesis of ME/CFS.
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.
In ME/CFS cases, the regression, Bayesian and enrichment analyses all revealed abnormal levels of several membrane lipids indicating dysregulation of the Kennedy pathway: decreased plasma levels of plasmalogens, phosphatidylcholines, phosphatidylethanolamines, sphingomyelins, and phospholipid ethers. Enrichment analyses revealed decreased levels of cholines, ceramides and carnitines, and increased levels of long chain triglycerides, dicarboxylic acids, hydroxy-eicosapentaenoic acid, and the tricarboxylic acid cycle intermediates alpha-ketoglutarate and succinate.
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). Our findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight specific abnormalities that may provide insights into the pathogenesis of ME/CFS.
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