Surprisingly good outcomes for people who get ME/CFS after Mononucleosis (Glandular Fever)
Sometimes ME/CFS emerges after mononucleosis, or glandular fever. Simon McGrath shares results from a long-term follow-up study from Haukeland University Hospital in Norway...
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Mitochondrial damage and viral infection different symptoms in different people

Discussion in 'General ME/CFS News' started by Gerwyn, Apr 17, 2010.

  1. Gerwyn

    Gerwyn Guest

    Known triggers of mitochondrial disease
    Mitochondrial diseases can go undetected for many years, and many cases display an episodic course with relatively stable periods punctuated by abrupt degeneration that may coincide with an infection or other stress to mitochondrial function. One study in young children definitively diagnosed with mitochondrial disease found that 60% showed an episodic disease course. In 72% of those cases, deterioration was associated with a naturally acquired infection

    The effects of mitochondrial disease can be quite varied. Since the distribution of the defective mitochondrial DNA may vary from organ to organ within the body, and each mutation is modulated by other genome variants, the mutation that in one individual may cause liver disease might in another person cause a brain disorder. The severity of the specific defect may also be great or small. Some minor defects cause only "exercise intolerance", with no serious illness or disability. Defects often affect the operation of the mitochondria and multiple tissues more severely, leading to multi-system diseases.

    central nervous system manifestations of mitochondrial disease can include hypotonia, seizures, encephalopathy, ataxia, intellectual disabilities, global delay, and brain malformations. Sensory and peripheral nerves can also be affected, leading to deafness, blindness, or neuropathy.
     
  2. darkrobot

    darkrobot

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    How do you find out if you have mitochondrial disease? Is there any treatment available? Is mitochondrial disease related to the mitochondrial dysfunction that Dr Myhill writes about?
     
  3. Gerwyn

    Gerwyn Guest

    yes it is there is a test to measure oxidative phosphorylation.

    I will post some info later if that is ok
     
  4. lotusflower

    lotusflower

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  5. Gerwyn

    Gerwyn Guest

    There are an increasing number of aquired mitochondrial diseases being accepted.Type I diabetes for example is one of them
     
  6. lotusflower

    lotusflower

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    Yes I do agree with you, the girl Hannah Poling won a million dollars award for mmr vaccine damage because of mitochondirial disorder although she won the award on the basis that she had an underlying genetic disorder, but I read an article by her father Jon Poling a neurologist in the autism file on mitochondrial dysfunction and disease and he said there was more and more evidence that they are acquired, I don't think they would have won the case if they said that. It is all politics

    I didn't know diabetes 1 was a mitochondrial disorder,but it makes sense, my sister has diabetes type 1. I have mito dysfucntion as per dr myhill tests. and I did get some weird blood sugar levels that were erratic, but was not confirmed as diabetes type 1, because one of them came back normal

    Do they recognise acquired mito disorders in the UK anywhere do you know
     
  7. Gerwyn

    Gerwyn Guest

    yes increasingly diabetologists renal physicians i have the list somewhere i will try to post it
     
  8. lotusflower

    lotusflower

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    Oh cheers thanks
     
  9. John Day

    John Day

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    Mitochondria is called the 'powerhouse of the cell'. It provides us with the energy for sustained exertion and is fundamental to the problem of CFS. Mitochondria produces Adenosine Tri-phosphate (ATP or stored energy) in conjunction with oxygen. When there exists an insufficient supply of energy, ATP is converted into Adenosine Di-phosphate which is then expressed as energy.
    Mitochondria is also implicated in neurological disorders and immune disfunction. The CNS nerves generate myelin through oligodendrocytes fueled by mitochondria. The Peripheral Nervous System generates myelin through Schwann Cells which too are fueled by mitochondria.
    Immune disfunction may also be caused by mitochondrial depletion as 50% of all of our mitochondria gets expended on immunity.
     
  10. Cort

    Cort Phoenix Rising Founder

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    A recent study that looked a mitochondrial performance during exercise suggests that the mitochondria are not dysfunctional - but that something else is impeding their activity. Any ideas?
     
  11. richvank

    richvank Senior Member

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    Hi, Cort.

    To which recent study are you referring?

    When you say that the mitochondria are "not dysfunctional," what do you mean exactly? What is the distinction between them being dysfunctional and having their activity impeded?

    Are you referring to genetic mutations in the mitochondrial DNA (what has come to be called mitochondrial disease)? If so, I agree that in most cases of M.E./CFS the mitos are dysfunctional, rather than suffering from inherited genetic mutations.

    My reading of the literature and numerous AcumenLab test results on PWCs suggests to me that there is abundant evidence of mito dysfunction in CFS.

    In addition, I believe that glutathione depletion combined with a partial block in the methylation cycle is able to explain all the observed evidence so far.

    Dr. Myhill and colleagues published a paper showing a correlation between lab testing showing mito problems and degree of disability in M.E./CFS. AcumenLab finds the following problems in the mitochondria of PWCs: damage due to oxidative stress, buildup of toxins (including heavy metals and hair dye chemicals) which block enzymes and serve as adducts on the mito DNA, deficiency of magnesium in the mitos, often deficiency of zinc, excess calcium, and rise in lactic acid, deficiency of carnitine, deficiency of coenzyme Q10, all of this resulting in low ATP production.

    Garth Nicolson's work shows low electrical potential across the mito membrane in M.E./CFS, indicating mito dysfunction. Dr. Hokama's test as well as Dr. Shoemaker's testing indicates elevated cardiolipin in M.E./CFS, which indicates oxidative damage to the mito membranes. There is also electron microscope data in the literature showing damaged mitochondria.

    All of the above can be accounted for by glutathione depletion combined with a partial block in the methylation cycle. For details of the biochemistry linking these features, please see my 2007 IACFS poster paper. I think it's still on your site, as well as at www.cfsresearch.org by clicking on CFS/M.E. and then on my name.


    Best regards,

    Rich
     
  12. John Day

    John Day

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    "which block enzymes"

    An enzyme is a complex protein molecule which acts as a biological catalyst in the process of creating ATP (Adenosine Tri-phosphate i.e Stored Energy).

    The purpose of an enzyme is to accelerate chemical reactions and, by means of this process of speeding-up, produce untold greater quantities of ATP. One study claims that without enzymes some chemical reactions would take 18,000 years.
     
  13. Cort

    Cort Phoenix Rising Founder

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    I think I'm going to learn something here :cool::cool:

    This is from an article I'm writing on the Vermoulen study

     
  14. WillowJ

    WillowJ Senior Member

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    The Vermeulen study could find no defect in two enzyme complexes of the mitochondria.

    However, the mitochondria requires an ion gradient in order to work properly. We do have replicated data that our ion channels are defective. If the ion channels in the mitochondrial membranes are leaky, the enzyme complexes themselves could be perfectly fine, yet the mitochondria dysfunctional because the necessary proton gradient isn't maintained. This would be the low electric potential mentioned by Rich.

    Or there could be a hundred other reasons why. The electron transport chain is quite complex, and the two enzymes they mentioned are important but there are multiple other components, all required for proper function.

    Electron photography is a much better indicator than a test of two enzymes.

    On the electron transport chain and making ATP, see:
    http://www.sp.uconn.edu/~terry/images/anim/ETS.html (quick overview)
    http://www.johnkyrk.com/mitochondrion.html (more detailed)

    Note something left out which is not relevant to ETP and ATP synthesis but is relevant to this discussion: there are other channels in the membrane in addition to ATP sythase. These normally are able to regulate the flow of ions and maintain the proton gradient. However, if they are defective, they can allow ions such as H+ to leak through.
     
  15. WillowJ

    WillowJ Senior Member

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    of course, it could be ATP sythase itself also which was defective. The studies I've seen full texts to did not mention which particular ion channels were defective.
     
  16. WillowJ

    WillowJ Senior Member

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    I've been going over the full text trying to figure this out. Seeing that they took blood out and actually tested the mitochondria to see how they worked had me confused for a bit. With any mitochondrial dysfunction, they should have gotten a different result (even though with n=15 it's not a very important study) even if it was an ion channel problem.

    I found something which has me curious.
    Did they take the blood for mitochondria tests only once? By the immune activation theory, they may have missed some disruption (something that, say, binds to an ion channel and changes the shape, making it dysfunctional) to mitochondrial dysfunction which occurred later.
     
  17. Cort

    Cort Phoenix Rising Founder

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    I knew I was going to learn something :cool::cool::cool::cool:

    I know who to go to for mitochondrial info. :Retro smile:
     
  18. WillowJ

    WillowJ Senior Member

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    I think I was wrong there. As far as I can tell, they assessed mitochondrial function only by testing products of those two enzymes, just like they said in the abstract. So I was right the first time. Action of those enzymes not necessarily relevant to ATP synthesis, if there's a problem affecting some other part.

    The part about immune activation might still be relevant, though, since at least one of the studies said ion channel activity was worse after activity.

    Sure, that's my field. :Retro smile: Bachelor degree only (thanks, ME; however my university took the program a good bit farther than most), in biology with unofficial emphasis in cell biology.
     
  19. lucy

    lucy Senior Member

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    I suspect looking into 'NO and mitochondria' might give some leads, for example here , as well as checking ideas as NMDA system dysfunction etc.

    Currently I am reading into the microvessel endothelium dysfunctions and possible link with ME/CFS. I am interested in this because since teenage I have raynnaud's. In raynnauds NO production is abnormal. If one looks into what excessive NO does to the body, many symptoms are ME/CFS.

    Some sources say, that ME/CFS, fibromyalgia patients often have Raynnauds. Interesting, but not informative - wiki says 25 percent of ppl have it, so in order that statement to be significant, we need more than 25. Also, many patients develop raynnauds after CFS or fibro onsett, not before. And researchers still have few clues what causes raynnauds, so it is not possible to know if people have something allready before developing raunnauds, or bam and you have it due to some environmental event in yr life.

    Also from my experience, if I eat something that produces gas in my bowels, I feel at least two times worse than before eating it. So according to my simplistic and dilentantistic thought of line, gas is very very evil, and it is capable of wreaking ATP cycle.
     
  20. richvank

    richvank Senior Member

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    Hi, Cort.

    I've now read the full Vermeulen et al. paper. Here are some comments:

    1. In their study, the cells were stored with DMSO (dimethyl sulfoxide). This is a very good antioxidant, and is able to cross cell membranes and enter cells readily. It very likely eliminated the oxidative stress that the cells were under when they were in the bodies of the PWCs. This is a very important point, since oxidative stress is well established in CFS, as the authors noted, and there are mechanisms built into the mitochondria to limit the rates of flow through both the Krebs cycle and the respiratory chain in response to oxidative stress. It has been suggested that this is a protective mechanism to limit the damage that would occur if these rates were not limited. There is published literature in support of this mechanism. As you may recall, in the GD-MCB hypothesis, I have suggested that depletion of glutathione, which is intrinsic in oxidative stress, is a major factor leading to mito dysfunction. DMSO could have compensated for low glutathione with the sample handling used in the Vermeulen study, rendering its results for the activities of the respiratory chain enzymes spurious.

    2. The level of creatine kinase in the blood plasma was used as a measure of oxidative phosphorylation, based on a study involving a genetic mitochondrial disease. The creatine kinase level in the plasma is actually a measure of the rate of cell death. The relationship between the rate of oxidative phosphorylation and the rate of cell death may be quite different in the mito dysfunction of CFS compared with the genetic mito disease chronic external ophthalmoplegia. This is certainly not a very direct measure of the rate of oxidative phosphorylation. The methods used by Dr. John McLaren Howard of Acumen Lab in the UK are more direct measures of the processes occurring in the mitochondria. As a related point, the creatine system in CFS is not operating normally, since the synthesis of creatine is normally the major user of methylation in the body, and we have found by lab testing that there is a partial block in the methylation cycle, leading to a methylation deficit. Based on urine creatinine measurements (which are usually low in PWCs), it seems likely that the creatine synthesis is low, which would be consistent with the observed methylation deficit. In view of this, it may well be that the expression of creatine kinase, which is the enzyme that reacts creatine with phosphate, is abnormal in CFS as well.

    3. I agree with WillowJ that the parameters measured in the Vermeulen et al. study would not give a complete picture of mito function, even if the issues discussed above were not present. An example of another aspect that can be observed readily is the levels of the Krebs cycle metabolites in the urine, as seen in urine organic acids testing, such as with the Genova Diagnostics Metabolic Analysis Profile (MAP). I have seen results of this panel from a large number of PWCs over the past several years, and it is unusual to find these levels close to their midranges. When glutathione is seriously depleted, there is a partial block at aconitase in the Krebs cycle, and this causes the citrate level to be high relative to those that follow it, which are downstream of the partial block at aconitase. This is a feature I have seen many times. In some other cases, I have seen very low levels for all the Krebs metabolites, and these people have very serious mito dysfunction and very low energy levels. This is usually accompanied either by low plasma amino acids levels or a deficit in vitamin B6, or both, which cause the rates of anaplerosis to be low. (Anaplerosis or "filling up" is the process by which the amino acids normally replenish the metabolites of the Krebs cycle.)

    3. The alternate explanation for the insufficient energy production in CFS that was offered by Vermeulen et al. is not tenable in the light of the (unfortunately unpublished) results of pulse oximetry during breath holding and IVRT measurement during application of additional oxygen by mask that Dr. Cheney has observed. Here is a description of what he has reported:

    When he attaches a pulse oximeter to the finger of a PWC and asks them to hold their breath for 30 seconds, he finds that they start with a % oxygen saturation in their arterial blood that is in the normal range (95-98%), and then he finds that it does not drop very much or at all during the breath holding, compared to normal, healthy people, in which it does drop. This indicates that sufficient oxygen is being carried by the blood, but that the cells are not utilizing it.

    When he sets up to monitor the IVRT (isovolumetric relaxation time) on the echocardiograph, and then gives supplementary oxygen by mask to a person with CFS, he finds that the IVRT increases, as compared with normal, healthy people, in which it does not increase. The IVRT is a measure of diastolic dysfunction, which is caused by insufficient rate of ATP production by the mitochondria of the heart muscle cells. This indicates that the mitochondria are not being limited by insufficient oxygen. Rather, they are self-limiting due to oxidative stress, and if more oxygen is added, the degree of oxidative stress becomes worse, thus causing more severe mito dysfunction.

    About 3 years ago, Dr. Sarah Myhill and I wrote a review of all the published CFS literature we could find pertaining to mitochondrial dysfunction in CFS. We submitted it to the journal Medical Hypotheses, and it was rejected. We then submitted it to the journal Mitochondrion, and it was also rejected. We, of course, believe that the paper has merit, and we may try again in response to papers such as the one by Vermeulen et al. As you can probably imagine, I think it is very unfortunate that it is so difficult to get a review of this type published, when the journals are frequently ready to accept papers involving CFS that contain serious errors (or the ones that imply psychiatric problems in CFS).

    Here is the abstract of our draft paper:

    Abstract

    This paper reviews the evidence that mitochondrial dysfunction is an important part of the pathophysiology of at least a major subset of the population who have chronic fatigue syndrome (CFS). Several types of published supporting evidence are cited, including the following: 1) muscle biopsy and ultrastructural examination; 2) status of mitochondrial nutrients and response to their supplementation; 3) gene expression studies; 4) indicators of abnormal processing of substances that are inputs to the mitochondria; 5) indicators of abnormal production of mitochondrial outputs; 6) apoptosis behavior; 7) heart function; 8) symptoms related to particular organs; and 9) intolerance to fatiguing exercise in CFS. We conclude that there is evidence for mitochondrial dysfunction in cells of the skeletal muscles, the immune system, the brain and the heart in at least substantial subsets of the CFS population. This conclusion points to a need to explain the cause or causes of mitochondrial dysfunction in CFS. It also points to the importance in both CFS research and clinical diagnosis and treatment of performing mitochondrial tests and of measuring levels of ATP. Other features important to the assessment of mitochondrial function should also be measured: nutrient levels, thyroid-related parameters and urine organic acids levels, including the levels of lactic and pyruvic acids, Krebs cycle intermediates, ketones and abnormal fatty acid metabolites.


    I will forward the Vermeulen et al. paper to Dr. Howard, and will let you know if he responds. I note that this paper is critical of his work, so I expect that he will have some thoughts to share! :)-)


    Best regards,

    Rich
     

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