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Dysregulation of the Kennedy Pathway and Tricarboxylic Acid Cycle in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2021, Lipkin,Hornig et al

Discussion in 'ME/CFS research' started by Sly Saint, Jun 23, 2021.

  1. Sly Saint

    Sly Saint Senior Member (Voting Rights)


    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.

    Last edited by a moderator: Jun 23, 2021
    Barry, Milo, Forbin and 27 others like this.
  2. cassava7

    cassava7 Senior Member (Voting Rights)

    It seems interesting that they found disturbances with lipids and reduced cholines, given the similar results from Hanson's team.

    As for the machine learning algorithm, unfortunately:
    ETA: "Multiple comparisons over all metabolites were corrected using the Benjamini-Hochberg procedure controlling the false discovery rate (FDR) at the 0.15 level."

    The cohort was fairly well characterized. All of the 106 patients and 91 controls were assessed according to both the Fukuda and Canadian consensus criteria, and they were screened with multiple questionnaires: DePaul Symptom Questionnaire, SF-36, Multidimensional Fatigue Inventory, Pittsburgh Sleep Quality Index. Unlike Hanson's study, the patients and controls were not only recruited from Sue Levine's office in New York, but also from Incline Village (Simmaron Research), Palo Alto (Stanford ME/CFS clinic?) and Miami (Nancy Klimas?).

    The main results are these two figures comparing the differences in metabolites between ME/CFS patients vs controls (in the legend of the bar chart, the variable p appears to be the estimated coefficients from Table 2). Most of the differing metabolites were complex lipids, none were primary metabolites.

    It seems that for a non-negligible number of patients, having their blood drawn was a demanding activity that they had to plan for. From the BA panel, they had taken paracetamol (acetaminophen) and Xanax (alprazolam) on the day they had their blood drawn. Combining this with referral bias, as the recruitment sources were tertiary care centers, the patients likely had severe or moderate ME/CFS. As could be expected too, some were being treated with the antiviral acyclovir.


    Last edited: Jun 23, 2021
  3. cassava7

    cassava7 Senior Member (Voting Rights)

    Here is the discussion about the Kennedy pathway, which seems to relate to mitochondrial function (bolding mine).

    The Kennedy pathway is responsible for the biosynthesis of phosphatidylcholines (PC) and phosphatidylethanolamines (PE), the two most abundant phospholipids in mammalian cells. (...) PC and PE are essential to the formation of intermediate structures in membrane fusion and fission events, for stabilizing membrane proteins into their optimal conformations, and for actin-filament disassembly in the end stage of cytokinesis. In people with ME/CFS, we found decreased levels of PC and PE and their downstream products: ceramides, sphingomyelins, lysophosphatidycholines, phospholipid ethers, prostaglandin D2 (PGD2) and prostaglandin F2α (PGF2α).

    One critical functional implication of reduced levels of PC and PE is impaired oxidative phosphorylation. PC depletion specifically affects the function of inner membrane protein translocases of mitochondria, including the TIM23 complex. PE synthesis is critical for cytochrome bc1 complex III function in the mitochondrial inner membrane. Preprotein binding to the TIM/TOM complex, which translocates proteins produced from nuclear DNA through the mitochondrial membrane for use in oxidative phosphorylation, is disturbed in PE-deficient mitochondria. Cytochrome c oxidase activity in the respiratory chain complex is also decreased with PE-deficiency. Reduced import of PE into the mitochondria results in the formation of respiration deficient cells, and in mitochondrial dysfunction. Finally, reduced levels of lysophosphatidycholines and phospholipid ethers, as well as of PC and PE, can impede mitochondrial respiration. Reduced synthesis of PGF2α and PGD2 in phospholipase A2γ-deficient mice induces mitochondrial dysfunction as well as oxidative stress that can contribute to further mitochondrial damage.

    Because PE and PC, and downstream metabolites in the Kennedy pathway, are important components of the lipid bilayer, the reduction in their levels has implications for signaling. Alteration in the levels or conformation of membrane components can adversely affect the functionality of proteins embedded in the membranes such as G protein coupled receptors (GPCRs). Phospholipids can act as direct allosteric modulators of GPCR activity through the lipid head group that affect ligand binding (agonist and antagonist) and receptor activation. For example, PE favors antagonist binding and stabilizes the inactive state of the receptor, whereas phosphatidylglycerols favor agonist binding and activation. Both PE and PC are precursors to many biologically active molecules that can act as second messengers. Prominent among them are Di-acyl glycerol (DAG), fatty acids, phosphatidic acid, lysophosphatidic acid, N-arachidonylethanolamine, N-palmitoylethanolamine, N-steroylethanolamine and arachidonic acid. Ceramides, are not only structural components of membranes, but can also act as second messengers in modulating a range of cellular signaling pathways.
  4. mariovitali

    mariovitali Senior Member (Voting Rights)

    Barry, Perrier, Amw66 and 2 others like this.
  5. cassava7

    cassava7 Senior Member (Voting Rights)

    On second thought, could the observed metabolic differences between ME/CFS patients and healthy controls be related to physical activity? The study does not indicate that both groups were matched on PA.

    I do not know if any data on the influence of physical activity on the Kennedy pathway and the TCA cycle can be found in the literature.
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  6. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

    It is possible.
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