Apart from high NADH/H+, ATP and acetyl-CoA, what inhibits the pyruvate dehydrogenase is a lack of cofactors (vitamin B1,B2,B3,B5, alpha lipoic acid, Mg, Ca).
Ca2+ at physiological concentrations was found to regulate dehydrogenase enzymes of mitochondria: glycerophosphate dehydrogenase
[5], responsible for shuttling reducing equivalents from cytosolic NADH into mitochondria, and the mitochondrial matrix dehydrogenases pyruvate dehydrogenase (PDH)
[6], isocitrate dehydrogenase (ICDH)
[7] and oxoglutarate (or α-ketoglutarate) dehydrogenase (OGDH)
[8]. Thus Ca2+ stimulates both glycogen breakdown and glucose oxidation leading to increased ATP supply.
https://www.sciencedirect.com/science/article/pii/S000527280900036X
Calcium signaling has been implicated as a mechanism that enables the body to increase energy production when requirements rise like during exercise.
One enzyme that is important for releasing calcium from the endoplasmatic reticulum is phospholipase C. It is activated by G proteins which use GTP/guanosine triphosphate.
Importance of breakdown of odd-numbered fatty acids and certain amino acids via propionyl-CoA to succinyl-CoA
Odd-numbered fatty acid rests and the amino acids valine, isoleucine, threonine and methionine can be broken down to propionyl-CoA and then succinyl-CoA dependent on cofactors like adenosylB12/hydroxo.
Succinyl-CoA enters the citric cycle where the first two reactions are:
1) succinyl-CoA+ GDP+Pi-> succinate + GTP + CoA-SH
2) succinate +FAD -> fumarate + FADH2
2) is coupled to the respiratory chain complex II and FADH2 then transfers its 2H+ and 2e- to QH2: picture
here
I think the balances of some substances (like ATP to NADH/H+ to GTP,..) are important and propionyl-CoA to succinyl-CoA increases GTP and FADH2 but only forms one NADH/H+ in the citric acid cycle. If you take the same route with pyruvate in the citric acid cycle, you get 4 NADH/H+ on one GTP and one FADH2. If high NADH/H+ is a potential problem by inhibiting the pyruvate dehydrogenase and increasing lactate production, the propionyl-CoA pathway produces relatively little NADH/H+.
Maybe this pathway can keep aerobic systems going longer by increasing GTP and calcium signaling, but not NADH/H+ that much.
My current idea is that some substances can accumulate and cause a jam, like high (cystosolic?) NADH/H+ or high acetyl-CoA, if other processes are functioning too low. Low GTP might work like that, inhibiting calcium signaling and I hope that the propionyl-CoA pathway might be a relevant pathway to get things moving along.
A typical example of such a pathway would be an inhibited repiratory chain in genetic disorders.
Calcium excretion can also increase glycerophosphate dehydrogenase activity.
Glycerol 3-phosphate dehydrogenase
NADH/H+ cannot simply pass through the mitochondrial membrane from cytosol to mitochondria. There are two shuttles that help transport NADH/H+ across the mitochondrial membrane the malate-aspartate-shuttle and the glycerol 3-phosphate shuttle:
https://de.wikibooks.org/wiki/Bioch..._Druckversion#Das_Glycerin-3-Phosphat-Shuttle
Glycerol-3 phosphate can take up two electrons and two protons from NADH/H+. Glycerol 3-phosphate can transfer the 2H+ and 2e- to FAD in the mitochondria forming FADH2.
Picture here:
https://en.wikipedia.org/wiki/Glycerol-3-phosphate_dehydrogenase#/media/File:GPDH_shuttle.png
This process reduces NADH/H+ back to NAD+ in the cytosol and increases FADH2 in the mitochondria which can transfer its 2H+ and 2e- to Q10 forming QH2. This can increase ATP production.
This might be one process that is beneficial during exercise, as NADH/H+ is reduced and it can’t form lactate anymore and ATP is increased which is important for higher ATP requirements during exercise. More GTP in the citric acid cycle might increase this process due to more calcium release.
pH and ME/CFS
At the moment I think that missing cofactor like calcium and high NADH/H+ in the cytosol due to defect transfer to the mitochondria might raise lactate production. There is too little citric acid cycle function in general which causes too low proton and CO2 production in the citric acid cycle. This might also be a reason why there was a too low increase in protons after exercise in ME/CFS patients (study a few posts up). Inhibited pyruvate dehydrogenase and low citric acid cycle function caused less conversion back from lactate to pyruvate (produces protons/ NADH/H+) and less activation of citric acid cycle proton production, while healthy people switched back to the aerobic system more.
Also, I think citric acid cycle function might be lower in ME/CFS compared to genetic defects in the respiratory chain. People with these defects might have higher NADH/H+ and develop lactic acidosis more.
Low HCO3- might be due to elevated lactic acid and due to low carbon dioxide production in the citric acid cycle. I think the processes that use HCO3- might also be reduced so I don’t know if an actual deficiency is visible, because it isn’t used up (?).
Processes that use HCO3-: Fatty acid synthesis, pyruvate carboxylase for pyruvate to oxaloacetate in gluconeogenesis, conversion from propionyl-CoA to succinyl-CoA (pathway
here, although one enzyme (
KEGG,
wikipedia) is wrong, uses HCO3- not CO2), pyrimidine synthesis, ammonium breakdown (carbamoylphosphate synthesis), breakdown of leucine.
I also liked this picture on page 165 figure 9.1
https://books.google.se/books?id=q8aVVxGjYnEC&lpg=PP1&hl=de&pg=PA165#v=onepage&q&f=false
It shows the importance of calcium and that branch-chained amino acids are low in muscle fatigue. I thought maybe this supports that amino acids like isoleucine and valine are important in exercise.
I might correct this post, haven't thought it over that much yet
.....
Addition:
Even if the respiratory chain doesn't work enough, GTP production alone can raise ATP. The nucleoside diphosphate kinase (NDPK) can transfer a phosphate group from one nucleoside triphosphate to another nucleoside diphosphate:
XDP + YTP ←→ XTP + YDP
ADP + GTP ←→ ATP + GDP
NDPK activities maintain an equilibrium between the concentrations of different nucleoside triphosphates such as, for example, when
guanosine triphosphate (GTP) produced in the
citric acid (Krebs) cycle is converted to
adenosine triphosphate (ATP).
[1] Other activities include cell proliferation, differentiation and development,
signal transduction,
G protein-coupled receptor,
endocytosis, and
gene expression.
https://en.wikipedia.org/wiki/Nucleoside-diphosphate_kinase
This might help balance ATP and calcium. If ATP is too low and GTP is too high, calcium might rise too much. Then GTP can raise ATP, which can transfer calcium back out of the cell and into the endoplasmatic reticulum with ATPases.
This might be a special feature of this pathway/ GTP, in comparison to increasing function of the inositol triphosphate pathway, which raises calcium more in general.