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Nitric Oxide, Peroxynitrite, and the Impairment of Mitochondrial Replication in CFS

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Hip, Apr 5, 2011.

  1. Hip

    Hip Senior Member

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    The contents below have been moved here from another thread:

    The general discussion that follows is about: Dave Whitlock's ideas that insufficient mitochondrial replication within cells possibly underlies CFS symptoms. Old mitochondria do not work well, so if they are not replaced it leads to problems.


    --------------------------------------------- Hip Wrote: ---------------------------------------------​

    Dave Whitlock has an interesting theory that autism and CFS are underpinned by low nitric oxide in the brain. He thinks that low brain nitric oxide causes the behavioral changes found in autism, and to an extent, in CFS too.

    In addition, apparently, ambient nitric oxide levels control the rate of mitochondrial biogenesis - the producing of new mitochondria and replacement and removal of the older mitochondria in cells. Whitlock says that mitochondria in cells have a normal lifespan of a few months, and they get regularly replaced because they wear out pretty quickly.

    When mitochondria wear out, they become leaky (leaking out protons, which then lead to more reactive oxygen species being produced in the cell) and much less efficient. So there needs to be a constant process of creating new mitochondrial, and replacement and removal of the older ones in the cell (otherwise cellular production is impaired, and the amount of damaging reactive oxygen species being created in the cell goes up).

    Whitlock thinks that the supposed mitochondrial problems in CFS / autism come from a lowered rate of turnover of mitochondria, simply due (according to Whitlock) to levels of nitric oxide being low (since the nitric oxide level sets the mitochondrial turnover rate). This lowered turnover means that we are not replacing the old and leaky mitochondria.

    In others words, people with CFS / autism may be going around with damaged mitochondria, because their mitochondria are not getting renewed, due to low nitric oxide.

    Certainly a very intriguing idea.


    ---------------------------------------------- Cort Wrote: ----------------------------------------------​

    Thanks Hip! Very interesting. I look forward to looking up Whitlocks ideas - I hadn't heard of him before.

    I think several of the parties believe that mitochondrial functioning is low - the question is that due to something outside mitochondria impacting them (low NO, poor oxygen delivery to them, high ONOO levels) or is it due to problems inside the mitochondria themselves? I think thats an accurate distinction but am aware that it may not be :)


    ----------------------------------------------- Hip Wrote: -----------------------------------------------​

    I just came across Whitlock's autism/CFS ideas recently. He is actually from a chemical engineering background, and I think he started seriously studying biochemistry in his own time, in order to try to understand and remedy his asperger/autism condition, which he says has have made progress in doing, using some rather strange and unusual techniques to raise the body's basal nitric oxide (NO) level techniques which he thinks should also work for CFS.

    On the face of it, it seems that his low NO view of CFS is in contradiction with Prof. Martin Pall's high NO view of CFS. Whitlock even says on his blog that his view differs from Pall's view.


    ------------------------------------------ Joopiter76 Wrote: ------------------------------------------​

    If someone is interested in what NO and its reaction product peroxynitrite are causing in the body, then have a look at Pacher et al:. Nitric oxide and peroxynitrite in health and disease.

    If you need a short overview about diseases caused by peroxynitrite have a look at the tables. There is much much more evidence than Pall cited in his book, about the things that occur in CFS. So everybody with CFS should test for nitrotyrosine and if possible for tetrahydrobiopterin. All my results fit with Prof. Palls publications.

    If Ca flows into the cells much too much which is typical for CFS because of the NMDA receptor activity then Ca cant be buffered and so it binds to other proteins in the cells where it does not go away from very easily. So the Ca dependent NO-Synthases produce much more NO and use up the BH4 which all raises peroxynitrite which again stimulates NMDA and lowers ATP by inhibiting the respiratory chain. This again leads to an increase in NMDA activity because NMDA is ATP dependent so more Ca comes into the cell and so on. The CA also binds to proteins outside the mitochondria which can lead to a mitochondrial clumping and which affects the normal cell motility. So this could also be a reason why mitochondria cant duplicate as usual.

    Another point is the during duplication mitochondria are very very oxygen sensitive, they turn of their respiratory chain because the even in healthy people generated superoxide would damage the new and young mitochondrial membrane during division. So this may be another point why they cant replicate.
    Last edited: Mar 27, 2014
  2. Hip

    Hip Senior Member

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    That is extremely interesting Joopiter76. So just to sum up the sequence of biochemical events you mentioned above:

    NMDA receptor overstimulation

    Too much calcium enters cells

    Calcium binds to proteins in cells, and remains there

    This means calcium-dependent NO-synthases produce more NO, and this uses up BH4

    Both the above lead to raised peroxynitrite

    This stimulates NMDA more, and lowers ATP by inhibiting the respiratory chain

    This again leads to an increase in NMDA activity because NMDA is ATP dependent, so the vicious cycle continues.​


    In terms of interventions to try to get out of this vicious cycle, it would seem that NMDA-receptor blockers would be one thing. Magnesium is a pretty potent NMDA-receptor blocker, and by taking high doses of magnesium (by injection, or better, by transdermal application) as many people with CFS do, you will be reducing the NMDA receptor overstimulation that starts this vicious cycle.

    Also, since NMDA receptor overstimulation can (and probably does) arise in part from brain inflammation in CFS (chronic microglial activation outputs lots of glutamate, which stimulates the NMDA receptors), anything that reduces brain inflammation will also help lower the NMDA receptor overstimulation in this vicious cycle.

    Then taking antioxidant supplements that quench peroxynitrite is another intervention in this vicious cycle, which is what Prof. Martin Pall advocates, as I understand.

    I also wonder if there is anything that can be done to reduce the calcium intake into the cell during NMDA receptor stimulation. This presumably would also help exit this vicious cycle, if you could reduce the calcium intake somehow.

    Regarding what you mentioned about the exquisite oxygen sensitivity of embryonic mitochondria: any ideas of how to best protect newly-forming mitochondria from oxygen?
    Last edited: Mar 27, 2014
  3. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    Brain fog and poor cerebral perfusion which is common in cfs can be from vasoconstriction from not enough nitric oxide, i think it comes down to controlling the byproduct of nitric oxide, peroxynitrate, maybe with anti-oxidants b12 etc. Dont know if all this is straight forward though.

    cheers!!!
  4. Freddd

    Freddd Senior Member

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    There is a limiting factor not mentioned in the previous summary. So far I haven't succeeded at finding research references for it. However, I do have some directly relevant experience in the whole matter. During my 16-17 year long crash I had considerable muscular atrophy. I was quite unable to build muscle. I had zero exercise tolerance. I had to start my hoping to be aerobic rehabilitation at about 2 minutes with basically no tension on the Nordic Track ski machine. On methylb12 plus basics, I got up to 6-7 minutes, didn't increase muscle mass and could not for the life of me get an real conditioning going. I started adenosylb12. I had read up on mitochondria formation as prompted by exercise in slow twitch muscle fibers and the effect of doing so. Nowhere have I seen adb12 mentioned as a limiting factor in muscle formation but it very clearly is. Muscle wasting from severe b12 deficiency is part and parcel of the deficiency. It can be caused by loss of nerves such as has occurred in my feet. I'm talking about the leg and arm muscles, shoulders, chest and back. They were not numb and lacking nerves controlling them. My thigh muscle was no thicker than the thickness of my thumb. Nothing reversed it. Then virtually immediately upon taking adenosylb12 the muscles all started recovery of strength, bulk and exercise capacity. The only effect the adb12 could have been having due to it's function at the heart of the ATP generation was restriction on mitochondria generation for lack of adb12. When it became available it was as if a switch turned on, energy generation shot up, muscle mass increased, exercise capacity increased and every indication was that it was because of the removal of the cause of inhibited mitochondria formation. I would be interested in hearing any other reason how lack of adb12 could have inhibited muscle formation, caused exercise intolerance, atrophy of muscles and all the rest.

    Adb12 has a substantial effect on a whole lot of people with CFS/FMS. It's lack is involved in at least half of the muscle pain and other problems. Hycbl is not an effective replacement. Mb12 is not an effective replacement. Cycbl is not an effective replacement. Only adb12 with other cofactors allows regeneration of muscle tissue, restoration of exercise capacity and reasonably rapid increase of aerobic capacity. This is aided by l-carnitine fumarate in those lacking sufficient again indicating the mitochondrial involvement of adb12 and l-carnitine fumarate.
    xks201 and aaron_c like this.
  5. Hip

    Hip Senior Member

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    Hi Freddd

    I have read your interesting story of how only the active adenosylcobalamin and methylcobalamin forms of B12 help you (and that you speculate you may have some genetic reason for this).

    However, I have read that hydroxocobalamin is the form of B12 required for nitric oxide scavenging, or cyanocobalamin, which converts to hydroxocobalamin in the body.

    Any thoughts on this? Do adenosylcobalamin and methylcobalamin have nitric oxide scavenging abilities?
  6. Freddd

    Freddd Senior Member

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    Hi Hip,

    A substantial amount of mb12 would be converted to hycbl (OHcbl) as soon as it losses it's methyl group, which happens at first usage if not sooner. Then it has to receive another methyl group if it is to be useful as b12 The OHcbl goes into an equilibrium with H2Ocbl (aquacbl). The methylb12 is quite reactive. This attribution of NO scavenging to solely hycbl is because of the specific research done on hycbl, not because it has unique characteristics in that regard. Hycbl is "natural" because it is a naturally occurring intermediate form in the body, not because it acts as b12. It reacts chemically with cyanide (CN), nitric oxide (NO) and nitrous oxide (N2O). However, cycbl has to be converted to other forms first because with a +3 oxidation it doesn't easily react with anything else without energy expensive uphill conversions requiring an enzyme. Mb12 to hycbl goes from +1 to +2 and does not require extra energy input to occur. Part of the problem with mb12 is that it is fragile because the +1 bond is weak and it just naturally breaks down to OHcbl and H2Ocbl in an aqueous solution, especially with a little light exposure to break the bond. Just putting it in solution is enough to cause some of the breakdown.
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  7. Hip

    Hip Senior Member

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    Freddd, how do you view this idea of Dave Whitlock that CFS/autism is due to low nitric oxide (NO), and in which case, do you think we might want to be careful about nitric oxide scavenging?

    The reason this Whitlock idea is fairly compelling is that CFS symptoms are near identical to the symptoms of hypothyroid disorder, in which the thyriod hormone tri-iodothyronine (T3) is low.

    Now this T3 hormone has a profound influence on mitochondrial biogenesis (creation of new mitochondria).

    So if, as Whitlock says, NO also has a profound influence on mitochondrial biogenesis, it stand to reason that the symptoms of low NO would be very similar to the symptoms of hypothyroid.

    In other words:

    Hypothyroid Disorder = low T3 => low mitochondrial biogenesis => fatigue, brain fog, etc -- this is known

    Chronic Fatigue Syndrome = low NO => low mitochondrial biogenesis => fatigue, brain fog, etc -- this is the speculation


    (Edit: Correction: I meant to say HYPOthyroid, not HYPERthyroid as I originally wrote here. I have corrected this error in this comment.)
  8. Freddd

    Freddd Senior Member

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    Hi Hip,

    Only problem is that CFS has a lot of HYPOthyroid. The fatigue of chronic fatigue is reversed very quickly for many with adb12 and l-carnitine fumarate and then exercise to promote muscle repair and mitochondrial formation. If more NO is needed Viagra and Cialis with appropriate exercise might be just the thing. The brainfog is gnerally cleared up very well by mb12, adb12, l-carnitine fumarate, Metafolin and a few other cofactors. In the Scarlet Pimpernel papers Dr Wheatly talks about b12 (hycbl since she is in the UK) being part of a regulatory feedback system controlling NO and reducing inflammation.

    T3 is more and more coming to be used to treat HYPOthyroid.

    And HYPOthyroid is often associated with autism, not HYPERthyroid.

    And I have seen kids with autism do very well indeed with adb12 and mb12. They, when a little older, say 8 years old or so, start responding to both adb12 and mb12 sublinguals before they are fully dissolved.

    And finally, low b12 appears to cause the autoimmune Hashimoto's hypothyroidism and is strongly associated with hypothyroid conditions in general, along with CFS and FMS. It takes BOTH mb12 and adb12 as well as methylfolate and L-carnitine fumarate with exercise to fully restore normal muscle function and relieve all the pain and problems in CFS/FMS.
  9. Hip

    Hip Senior Member

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    Naturally I meant to say hypothyroid, not hyperthyroid. An example of brain fog in action! Even though I triple check my comments for errors, I can't see the obvious ones.

    Technically, people properly diagnosed with CFS should have been tested for hypothyroid, since hypothyroidism is one of the things a doctor needs to exclude before you can be given the CFS diagnosis.

    However, I know hypothyroidism can be complicated (some people with hypothyroidism, for example, take the T4 (thyroxine) hormone replacement, which the liver is then suppose to covert to T3, but they still do not feel right, and some hypothyroid patients need to take T3 as well as T4, for some reason - perhaps their liver is not up to scratch).

    After reading Whitlock's ideas of low NO, it occurred to me that perhaps CFS might involve some more obscure form of hypothyroidism. Where they may be enough thyroid hormones in the blood, so the tests come back normal, but somehow these hormones are not working when they reach the cells. (Like there is diabetes from lack of insulin, and diabetes from lack of sensitivity in the insulin receptors - insulin resistance).

    Maybe there is an obscure failure in the T3 hormone system in some cases of CFS, which might lead to reduced mitochondrial biogenesis? I did try some T3 supplementation (10 mcg a day) as an experiment in generating new mitochondria, but the only change I felt was more anxiety symptoms.

    I do well on ordinary L-carnitine, high-dose transdermal magnesium, and B12 helps me a bit (any B12 form seems to work in my case). I have taken high doses of 5 mg adenosylcobalamin and 5 mg methylcobalamin simultaneously (applied over my skin, where you can get up to 6% B12 absorption, I read in a study), but in my case, I get the impression that hydroxocobalamin may be just as good. I have not tried L-carnitine fumarate, but will look into it.
  10. Freddd

    Freddd Senior Member

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    Hi Hip,

    If you haven't tried the Enzymatic Therapy or Jarrow held for 45-120 minutes you haven't tried methylb12. We are accustomed to getting 15-25+% absoption with these as verified with trials compared to injections. Further they are qualitatively superior, excellent compared to other brands of mb12 of any form. Thjey are a good 100-10,000 times more effective than hydroxycbl. Without the adb12 adequately absorbed with the l-carnitine fumarate, the mitochondria can't work no matter what your thyroid status is.
  11. Lee Ann

    Lee Ann

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    Question...
    Is this the same thing NO that is used in surgery ?? Just curious b/c of surgery I had and did not know my B12 was low..Later found out that can be dangerous...NO can deplete your B12
  12. Hip

    Hip Senior Member

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    No, it is not the same. You are thinking of nitrous oxide, which has the formula N2O. Also known as laughing gas. N2O is a potent NMDA receptor inhibitor, though, and I have often wondered whether it might help (for different reasons) in CFS, in order to calm the NMDA overestimation.
  13. Hip

    Hip Senior Member

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    The methylcobalamin B12 brands that I tried are Wonder Labs Sublingual B12 (5 mg per tablet), and Holistic Heal liquid B12 ( 1mg per drop). Any idea if these are effective?

    I find sublingual difficult to do, since I find I produce and swallow my saliva all the time, though I have taken the methylcobalamin drops intranasally (where I imagine you probably get slightly better absorption than sublingual); you can put around 5 drops per nostril via a dropper pipette (any more, and it tends to run down the back of the throat) - so that is a total of 10 mg of methylcobalamin in the nose.

    I found these B12 absorption studies a while back:

    Nasal absorption of hydroxocobalamin in healthy elderly adults
    Percutaneous Absorption of Vitamin B12 in the Rat and Guinea Pig
  14. drex13

    drex13 Senior Member

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    After reading Whitlock's ideas of low NO, it occurred to me that perhaps CFS might involve some more obscure from of hypothyroidism. Where they may be enough thyroid hormones in the blood, so the tests come back normal, but somehow these hormones are not working when they reach the cells. (Like there is diabetes from lack of insulin, and diabetes from lack of sensitivity in the insulin receptors - insulin resistance).

    Maybe there is an obscure failure in the T3 hormone system in some cases of CFS, which might lead to reduced mitochondrial biogenesis? I did try some T3 supplementation (10 mcg a day) as an experiment in generating new mitochondria, but the only change I felt was more anxiety symptoms.


    My current doctor tested my thyroid function, among other things. She tested my T3 as well as my reverse T3. My normal T3 was low normal and my reverse T3 was high normal. She said this should be the other way around, if everything is functioning properly. So maybe your onto something here.
  15. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    When u start researching into hormones u begin to find yourself chasing your own tail, not a bad thing but how it is, trial and error to find what is wrong as there are many upstream hormones that effect many down stream hormones. If u think thyroid is a problem and are testing low, before adding thyroid i would look into adrenal fatigue and look into testing and replacing pregnenolone and or dhea as these adrenal hormones if low can negatively effect thyroid function and improving this can improve thyroid without having to dabble in thyroid hormones. The more down stream hormones u use the more problems can occur up stream. Pregnenolone and dhea dont have any negative feedback problems ie it doesnt stop your own body from producing its own hormones, unlike say thyroid or testosterone etc. So if dabble in thyroid and then worked out thyroid isnt the problem then u have the original problem and a new one which is trying to restart your thyroid. Test every dam hormone u can and start up stream with pregnenolone and work your way down as needed.

    cheers!!!
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  16. Freddd

    Freddd Senior Member

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    Hi Hip,

    N2O, nitrous oxide, used as part of many anesthesia schemes, from alone at the dentist to making a resurgence in childbirth and general anesthesia as part of the mix, destroys mb12 in the brain and body, permanently oxidizing it. Of course with enough mb12 it is detoxed and removed from the body. In some people it can trigger a life threatening crisis. However, a single dose of a a 5 star mb12 can turn it around in minutes. It will after a short improvement cause a crisis/crash in many CSF/FMS persons. Low dose ketamine is being investigated for the purpose you mention and is very effective without destroying mb12 and almost certainly adb12 as well.
  17. Freddd

    Freddd Senior Member

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    Hi Hip,

    I and 4 other mb12 hypersensitives tested 10 brands 5-8 years ago. Two brands, Jarrow and Enzymatic Therapy, were incredibly superior. One brand was a total zero, Source Natural, and 7 other brands were very mediocre, not one of them able to even fully maintain the gains made by the 5 star brands much less make additional gains. The differences there were how relatively bad they were. In testing 5 batches of injectable mb12 one and over time another 30 or so, only a couple were excellent, several were pretty good and some were pretty bad. Most of them were so degraded by exposure to light that they were untestable as to the quality of the original MB12 and were terrible, hycbl equivalent because that is what mb12 degrades to with light.

    The trick to making them last 45-120 minutes is to put them under your upper lip and leave them there, don't suck them or chew them or anything. I did not test the brands you mention. However, the odds are against them being significantly good. You can tell us how they compare to the 5 star ones when you try them. Also, adb12, Metafolin and a lot of other cofactors are needed, no folic acid or folinic acid, no glutathione and/or precursors that can block active b12 and methylfolate activity.

    Read the basics at http://forums.wrongdiagnosis.com/showthread.php?t=62327 and then let's talk about it back here.
  18. Freddd

    Freddd Senior Member

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    Hi Heapsreal,

    You need to go further upstream. Low mb12 and cofactors affects all the hormones. Correct this underlying mb12/adb12/Methylfolate problem and most of the other things will normalize.

    Pregnenolone and DHEA fall off over about age 40. They can be helpful for some people.
  19. anne_likes_red

    anne_likes_red Senior Member

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    Shhhhh don't mention DHEA ;)

    Australian*grumble*customs*confiscated*grumble...

    Peroxynitrate: Taurine is a NMDA receptor inhibitor, peroxynirate scavenger and it gets magnesium into the cells. Anyone know if it gets calcium out?

  20. Freddd

    Freddd Senior Member

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    Hi Anne,

    You might see if you can bring it in with a letter from your doctor. Sometimes that is all it takes. Pregnenolone is better (in my opinion) anyway and is a step further back so may not be considered in the same light. Also, there might be a cofactor that works with cholesterol to generate pregnenolone that you could get if there is a problem with pregnenolone.

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