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NNT and NADPH in the mitochondria, NAD Recipe part 2

Discussion in 'General ME/CFS Discussion' started by Kimsie, Dec 3, 2014.

  1. Kimsie

    Kimsie Senior Member

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    This is really a continuation of NAD recipe, but I am introducing some important new ideas so I thought I would start a new thread.

    What I say here relates to my hypothesis that these illnesses (not only ME/CFS but some other chronic illnesses also) are caused by a vicious cycle of oxidative stress. I think I may have found the heart of the vicious cycle, and if I have, then it might be possible to overcome it.

    Next is the technical part:

    To get rid of H2O2, hydrogen peroxide, requires NADPH, which is used to return glutathione to its active state, and keep the GSH/GSSH ratio low. There are several mechanisms for recycling NADPH in the mitochondria: Malic enzyme, isocitrate dehydrogenase and NNT, or Nicotinamid Nucleotide Transhydrogenase.

    Here is a great illustration from an article found NNT.jpg here, which I have added some comments to clarify. You can see the electron transport chain on the upper right hand side and how it transfers protons (H+) to the intermembrane space of the mitochondria. These protons are used by ATP synthase (shown at the top right) to change ADP to ATP, and also by NNT to change NADP to NADPH. It seems that NNT is supposed to produce about half of the NADPH in the mitochondria, but you can see that if the electron transport chain is inhibited, as I believe that it is in these illnesses, there are not enough protons in the intermemberane space to produce energy and recycle NADPH.

    Since iron-sulfur cluster synthesis begins and ends in the mitochondria, and iron-sulfur clusters are damaged by H2O2, and iron-sulfur clusters are a critical part of the electron transport chain, we have a vicious cycle here. Is this vicious cycle at the heart of these illnesses? If it is, we might be able to overcome these illnesses by increasing the amount of NAD in the mitochondria high enough to increase the concentration of NADH to push the ETC and raise the proton gradient to a sufficient level to feed both the NNT and the ATP synthase enzymes.

    So this brings us back to the NAD recipe. I have some new information relating to that, and I will post on it later.

    One last thing, I should mention that although taking malic acid might increase synthesis of NADPH in the peripheral parts of the body through the malic enzyme as seen in the illustration above, it doesn't really cross the BBB.
     
    Last edited: Dec 3, 2014
  2. Kimsie

    Kimsie Senior Member

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    High dose niacin is known to cause elevated aminotransferases, particularly aspartate aminotransferase. I can't help thinking that this might be because niacin triggers the body to try to make more NAD, and aspartate is an ingredient in the NAD recipe, so aspartate might be the most common limiting factor after niacin or niacinamide and D-ribose, which are probably the most limiting factors.

    There are some warnings about the use of L-aspartic acid, because it can excite neurons in excessive amounts. However, in order to increase the amount of NAD in the body, an increase of aspartate is required. Here is the formula for aspartate aminotransferase: Aspartate (Asp) + α-ketoglutarate ↔ oxaloacetate + glutamate (Glu), so synthesis of aspartate could drain glutamate, another ingredient for NAD.

    So I have ordered some L-aspartic acid because I am going to use it in my attempt to increase the proton gradient in the mitochondria of D, my best subject for experimentation.

    Wouldn't it be nice to just be able to take a proton pill like Roger Ramjet? lol (old US cartoon from the 1960's.)
     
  3. adreno

    adreno PR activist

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    Magnesium aspartate could be another option.
     
  4. Kimsie

    Kimsie Senior Member

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    It a person takes 500 mg of elemental magnesium as magnesium aspartate, they would be taking 1.5 grams of aspartate, and probably absorb less than 750 mg because it is absorbed at less than 50 percent. So it is possible to get some aspartate that way, but probably not enough, but it's a good thought.

    I really don't see what difference it makes which form is used, except that if a person is low in magnesium, of course taking the magnesium will help because magnesium is used in several of the enzymes to make ATP, NAD, etc. The most important thing would be to balance the amounts of all the ingredients so that there would not be too much free aspartate at any time.
     
  5. Kimsie

    Kimsie Senior Member

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    I have made a new diagram of the powdered ingredients for ATP and NAD that takes into account the molecular weight and the amount of grams per teaspoon of the powders showing the balance of the amounts used in purine synthesis. For instance, there are twice as many molecules of glycine than ribose in a gram, so you only need 1/2 gram of glycine to match 1 gram of ribose. (But some people might already make enough glycine)

    The amount of aspartic acid is actually about 20% low to avoid excess. Sufficient amount of niacinamide are also needed. A person might want to take more than 100% of the amount of ribose if they tend to get detox from glutamine and glycine, in order to draw a larger percent of the glutamine and glycine into purine synthesis instead of synthesis of glutathione.
    NAD recipe2.jpg
     
  6. adreno

    adreno PR activist

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    melamine and ahmo like this.
  7. Kimsie

    Kimsie Senior Member

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    Well , you always want plenty of thiamine and magnesium for sure.

    I was just giving the ratios of the ingredients as they are used to make purines, and you can't make more ATP and NAD without making more purines. It doesn't mean that everyone should take exactly those amounts. If a person is experiencing excitotoxicity, they should take less glutamine and aspartic acid, for sure. Each person has to figure out their own particular needs by experimentation.
     
  8. adreno

    adreno PR activist

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    Right, but there might be adaptive reasons why those are low in ME/CFS.
     
    melamine likes this.
  9. Kimsie

    Kimsie Senior Member

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    Well, I think it is more likely that they are causative reasons.
     
  10. Kimsie

    Kimsie Senior Member

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    I finally figured out last night why taking NADH helped one person for 10 days and stopped working, and why coconut oil worked for a week for D and then stopped working. It's somewhat discouraging, but I think it can resolved by resting when you don't feel tired. It's just that it is so difficult to rest when you have energy, but that's what you have to do. It's sort of the opposite of graded exercise.

    (I can't remember if I posted about how I am pretty sure now that the inhibition of the ETC is caused by H2O2 (or oxidative stress) damage of the iron-sulfur clusters.)

    The problem is that when you push the electron transport chain with the NAD recipe, more H2O2 will be produced by the ETC while you increase the proton motive force which powers both ATP and NADPH synthesis in the mitochondria. Since the proton gradient is still limited, if you decide that since you feel so good you will get a lot of things done then you use too much of that proton motive force for ATP and you will not make enough NADPH to get rid of the H2O2, because NADPH is used to reactivate glutathione, and you will actually have more damage to the iron-sulfur clusters and a more inhibited ETC after about a week or even less, because the half-life of the ETC complexes is about 8 days and the new complexes will have more damaged iron-sulfur clusters than the old ones.
    Proton gradient problem.jpg If you stop using so much ATP, that should allow the proton motive force to be used to make NADPH and stop oxidative stress while you fix the iron-sulfur clusters. Taking pretty frequent doses of NAC should help the body to have the sulfur resources for fixing the clusters.

    So the idea is that you increase the proton motive force, and then use that increase for fixing the underlying problem, instead of using it for producing energy to get up and do things.

    Now if you can fix them while they are in place in the ETC complexes, it shouldn't take more than a day, but if you have to keep doing this until you make new ETC complexes, since the half-life is about 8 days, I guess you probably would have to rest for at least 8 days while taking the NAD recipe to improve the condition of the ETC enough to gradually start increasing activity. We are experimenting around with this, but D doesn't have a day he can really rest on until next Monday.
     
    Last edited: Dec 11, 2014
  11. Gondwanaland

    Gondwanaland Senior Member

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    I am having trouble in finding all the ingredients and the proportions... too many threads, too many posts, too many ingredients...

    Could you please summarize them, Kim?

    For my profile I don't want to raise uric acid, don't want to impair conversion of T4 to T3, I do better on niacin than on nicotinamide, I think I am undermethylator because methylcbl was the best thing I ever took, but overdosed on it and I think I can't halndle the detox reaction now. So no glutathione for me either... I'm a tough customer, I know...
     
  12. Kimsie

    Kimsie Senior Member

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    Is your uric acid high? Sorry if I have asked that before. Do you know if you B6 is high or low or normal? (I am gathering data about something I will post on soon.)

    I think the most important thing is the ribose, with the niacinamide being next for overmethylators but not undermethylators. Don't worry about the other things right now. In the last 4 days or so I have learned a lot of new things and I am having to change some of my ideas.

    I'm sorry that I keep changing things, but I am in a learning process, and it is so helpful for me to post here on PR because of all the comments you people give me, so I can't really just wait until I learn everything to start posting my ideas, because my ideas need help from you people here.
     
    Gondwanaland likes this.
  13. Gondwanaland

    Gondwanaland Senior Member

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    Yes, always on the high side, sometimes a little above range, and I have symptoms from it (not gout).
    I don't know, but after doing an aggressive magnesium supplementation I now always have complex dreams and dream recall.
     

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