https://www.sciencedirect.com/science/article/pii/S1567724918301053
The good news is that the dauer state in the worm model is completely reversible. If dauer is a good model for ME/CFS, then there is hope that by studying the molecular controls of the dauer phenotype, new treatments might be discovered rationally to help stimulate the exit from the dauer-like state and begin the process of recovery. The following is a summary of a plausible sequence of pathogenesis for ME/CFS. All stressed cells leak ATP through stress-gated pannexin/P2X7 and other channels. Extracellular ATP (eATP) signals danger and CDR1 is initiated (Fig. 1). If the acute cell danger response and healing cycle fail to eliminate the stress and stop the ATP leak by successful completion of CDR3, then an energy conservation program is activated. Normal cell activation pathways utilize lipid rafts and sphingolipid microdomains on the cell membrane to facilitate metabokine- and cytokine-receptor binding and signaling by receptor subunit dimerization. Sphingolipids are downregulated in most cases of ME/CFS (Naviaux et al., 2016) and may facilitate an energy conservation state.
The dauer-like energy conservation program in mammals may also involve a ligand-receptor desensitization process, decreasing the ability of cells to release intracellular calcium when needed. Calcium stimulates mitochondrial oxidative phosphorylation. When stimulated by ATP and related nucleotides, IP3-gated calcium release is decreased (Schmunk et al., 2017), and mitochondrial and whole cell reserve capacity is reduced. Other mechanisms for downregulating mitochondrial energy production can contribute to this energy conservation state. A multifactorial reduction in mitochondrial pyruvate dehydrogenase complex activity in ME/CFS has been described (Fluge et al., 2016). Upregulation of ectonucleotidaseslike CD39 and CD73 can increase the conversion of ATP and ADP to AMP and adenosine. Both AMP and adenosine bind adenosine receptors (Fig. 4A) and produce a reversible hypometabolic state in mice that is protective against many environmental stresses, including lethal irradation (Ghosh et al., 2017). Continued leakage of ATP to the extracellular space for CDR signaling also creates a source for the hypometabolic signaling molecules AMP and adenosine, while depleting intracellular reserves of ATP. Although not yet tested in a clinical trial in patients with ME/CFS, the ATP and UTP leak might be stopped by blocking the efflux of nucleotides through the pannexin/P2X7 channel with an antipurinergic drug, thereby unblocking the healing cycle (Fig. 1) and permitting recovery to begin. This is similar to a strategy recently tested in a clinical trial in autism spectrum disorder (Naviaux et al., 2017) and illustrated in a whiteboard animation available at:
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The good news is that the dauer state in the worm model is completely reversible. If dauer is a good model for ME/CFS, then there is hope that by studying the molecular controls of the dauer phenotype, new treatments might be discovered rationally to help stimulate the exit from the dauer-like state and begin the process of recovery. The following is a summary of a plausible sequence of pathogenesis for ME/CFS. All stressed cells leak ATP through stress-gated pannexin/P2X7 and other channels. Extracellular ATP (eATP) signals danger and CDR1 is initiated (Fig. 1). If the acute cell danger response and healing cycle fail to eliminate the stress and stop the ATP leak by successful completion of CDR3, then an energy conservation program is activated. Normal cell activation pathways utilize lipid rafts and sphingolipid microdomains on the cell membrane to facilitate metabokine- and cytokine-receptor binding and signaling by receptor subunit dimerization. Sphingolipids are downregulated in most cases of ME/CFS (Naviaux et al., 2016) and may facilitate an energy conservation state.
The dauer-like energy conservation program in mammals may also involve a ligand-receptor desensitization process, decreasing the ability of cells to release intracellular calcium when needed. Calcium stimulates mitochondrial oxidative phosphorylation. When stimulated by ATP and related nucleotides, IP3-gated calcium release is decreased (Schmunk et al., 2017), and mitochondrial and whole cell reserve capacity is reduced. Other mechanisms for downregulating mitochondrial energy production can contribute to this energy conservation state. A multifactorial reduction in mitochondrial pyruvate dehydrogenase complex activity in ME/CFS has been described (Fluge et al., 2016). Upregulation of ectonucleotidaseslike CD39 and CD73 can increase the conversion of ATP and ADP to AMP and adenosine. Both AMP and adenosine bind adenosine receptors (Fig. 4A) and produce a reversible hypometabolic state in mice that is protective against many environmental stresses, including lethal irradation (Ghosh et al., 2017). Continued leakage of ATP to the extracellular space for CDR signaling also creates a source for the hypometabolic signaling molecules AMP and adenosine, while depleting intracellular reserves of ATP. Although not yet tested in a clinical trial in patients with ME/CFS, the ATP and UTP leak might be stopped by blocking the efflux of nucleotides through the pannexin/P2X7 channel with an antipurinergic drug, thereby unblocking the healing cycle (Fig. 1) and permitting recovery to begin. This is similar to a strategy recently tested in a clinical trial in autism spectrum disorder (Naviaux et al., 2017) and illustrated in a whiteboard animation available at: