This post is based on a published study entitled "Metabolic features of chronic fatigue syndrome" by Naviaux et al. There is also an appendix with additional info. In particular, this appendix contains a nice detailed metabolic map (Figure S6).
The main conclusion of the paper is that CFS is consistent with a state of hypometabolism resulting from physiological stress to the cells (a cell danger response mechanism.) Based on this information, I am going to try to develop a strategy to get the system (in this particular case called me) out of this funky state.
In this first post I'm not going to address mitochondrial oxidative phosphorylation impairment, which I believe is also a major problem. I'll do that in a later post.
From the paper: "All of the metabolic abnormalities that we identified in CFS were either directly regulated by redox or the availability of NADPH. [...] When reduced (NADPH) and total (NADPH plus NADP+) pools are low, sterol, fatty acid, protein, and nucleotide synthesis fall to baseline survival levels. When NADPH levels are higher, metabolism is shifted from persistence to normal cell function and growth, anabolic pathways are stimulated, biomass is created, and carbons and electrons are stored as biopolymers for cell growth and repair in the form of lipids, protein, glycogen, glycans, and nucleic acids."
From this, one is tempted to conclude that increasing NADPH ad hoc is a winning strategy but the authors caution: "NADPH cannot be simply added as a nutritional supplement to produce the tidal change in metabolism needed to shift the dauer state of CFS to normal health." However, they hypothesize that "incremental improvements in NADPH production could theoretically be supported by interventions directed at folate, B12, glycine, and serine pools, and B6 metabolism (SI Appendix, Fig. S6)."
I spent a few hours looking at the metabolic map in Figure S6 (in the Appendix) and came up with the following conclusions:
Supplementing with these is far from a new or big revelation for many with CFS, considering that "methylation" has been for quite some time a hallmark of "treatment." But this is clearly not enough and addressing another variable in the hypometabolism equation is required. That variable is mitochondrial oxidative phosphorylation. I'll attempt to do so in a subsequent post. In any case, @Remy already addressed this in several of his posts.
The main conclusion of the paper is that CFS is consistent with a state of hypometabolism resulting from physiological stress to the cells (a cell danger response mechanism.) Based on this information, I am going to try to develop a strategy to get the system (in this particular case called me) out of this funky state.
In this first post I'm not going to address mitochondrial oxidative phosphorylation impairment, which I believe is also a major problem. I'll do that in a later post.
From the paper: "All of the metabolic abnormalities that we identified in CFS were either directly regulated by redox or the availability of NADPH. [...] When reduced (NADPH) and total (NADPH plus NADP+) pools are low, sterol, fatty acid, protein, and nucleotide synthesis fall to baseline survival levels. When NADPH levels are higher, metabolism is shifted from persistence to normal cell function and growth, anabolic pathways are stimulated, biomass is created, and carbons and electrons are stored as biopolymers for cell growth and repair in the form of lipids, protein, glycogen, glycans, and nucleic acids."
From this, one is tempted to conclude that increasing NADPH ad hoc is a winning strategy but the authors caution: "NADPH cannot be simply added as a nutritional supplement to produce the tidal change in metabolism needed to shift the dauer state of CFS to normal health." However, they hypothesize that "incremental improvements in NADPH production could theoretically be supported by interventions directed at folate, B12, glycine, and serine pools, and B6 metabolism (SI Appendix, Fig. S6)."
I spent a few hours looking at the metabolic map in Figure S6 (in the Appendix) and came up with the following conclusions:
- Methylenetetrahydrofolate is an important metabolic substrate for the production of NADPH both in and outside the mitochondria. In particular, it is a substrate for the production of methyltetrahydrofolate (aka, methylfolate) and this process is subject to those pesky genetic variations in the MTHFR gene many of us are already acquainted with;
- Tetrahydrofolate, the demethylated version of methylfolate, is an important cofactor in the production of methylenetetrahydrofolate via several pathways;
- Outside the mitochondria, tetrahydrofolate is created when it cedes its methyl group to cobalamin (B12) resulting in methylcobalamin, which in turn is used in the methylation cycle we all know and love. It may also be created from dietary folate via a sequence of reactions.
- Inside the mitochondria, tetrahydrofolate may also be obtained from folinic acid.
- Trimethylglycine is an important component in the methylation cycle and, as part of this cycle, it gets demethylated into dimethylglycine. Dimethylglycine is an important component for the production of methylenetetrahydrofolate.
- Methylcobalamin
- Methylfolate
- Pyridoxal phosphate
- L-glycine
- Trimethylglycine
- N-Acetylcysteine
Supplementing with these is far from a new or big revelation for many with CFS, considering that "methylation" has been for quite some time a hallmark of "treatment." But this is clearly not enough and addressing another variable in the hypometabolism equation is required. That variable is mitochondrial oxidative phosphorylation. I'll attempt to do so in a subsequent post. In any case, @Remy already addressed this in several of his posts.
