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Universal heteroplasmy of human mitochondrial DNA

Discussion in 'Other Health News and Research' started by anciendaze, Mar 4, 2016.

  1. anciendaze

    anciendaze Senior Member

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    While there are many indications something weird is going on with mitochondria in ME/CFS there have been real problems pinning down what is going wrong. In many ways we seem to age suddenly in response to a minor infection. This paper on more general characteristic of mitochondrial genetics, and not just inherited genes, seems relevant to the problem. All mitochondria are not equal.

     
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  2. anciendaze

    anciendaze Senior Member

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    Translation: If all humans have multiple mitochondrial genomes to begin with, you don't need mutations to cause apparent changes. Clonal expansion of rare variants could give the appearance of dramatic and unusual changes in mitochondrial genetics without any actual mutations. (Not saying they can't happen, just that you don't need to postulate them.)

    Assumptions about uniformity of mitochondrial genomes in an individual, or about limitation of changes to point mutations, are invalid. Apparent change may simply result from amplifying something already present. This corresponds to the distinction between defects and exposed faults I've been familiar with in quality control literature. Most ordinary genetic testing would not come close to the resolution needed to find the source of a problem before it becomes pathological. No wonder researchers haven't gotten far using earlier assumptions.
     
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  3. merylg

    merylg Senior Member

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    Sydney, NSW, Australia
    Also interesting is the higher levels of mito heteroplasmy found in muscle compared with levels found in blood.
     
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  4. lansbergen

    lansbergen Senior Member

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    Yep
     
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  5. anciendaze

    anciendaze Senior Member

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    This highlights a concern I've had with much next-generation sequencing: it is very easy to overlook low frequency sequences, and algorithms which fit the pieces back together may filter out implausible ones which would convey the greatest information if found.

    (I'm reminded of the NASA satellite which had sensors that seemed to go crazy when it passed over Antarctica in certain seasons. The observation that told the world about the huge ozone hole was made from the ground. It turned out the data reduction program used for satellite data had a test which refused to believe such readings were valid, and removed them. This went on for years.)

    The 454 platform this group used is now fairly old, but they went far beyond this base technology to find rare variants and confirm that these were not artifacts. The easy way out is to discard the least probable ones. I don't know to what extent other groups are pursuing comparable strategies to find rare variants of sequences. I do know that cheap sequencing tends to overlook them.

    Even rare variants expressed in only a few tissues, like skeletal muscles, have the potential to trigger a response which could affect healthy mitochondria elsewhere. If we had a progressive and lethal disease you could be sure there would eventually be lots of evidence of abnormal sequences -- when the disease killed patients. Since this disease is not generally lethal, there is a real chance the cause will be harder to find. Something must be working to keep us slightly alive. What is more, there is no guarantee the same sequences will turn out to be the problem in different individuals.

    This general problem shows up in virtually all the "Omics".
     
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  6. anciendaze

    anciendaze Senior Member

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    Still processing the change to my underlying assumptions based on the new evidence that heteroplasmy is the rule, not the exception. (Even healthy people generally have multiple mitochondrial genomes.) I may have run across an important idea.

    The general biological equivalent of amplification is called clonal expansion. We see this most commonly in behavior of immune systems. We also see this in progressive infectious disease, where the cells are either bacteria or infected host cells. We also see this in cancer. Until now, I had not realized clonal expansion of mitochondria could result in dramatic changes in characteristics without substantial new mutations. This is important because there are typically thousands of mitochondria for each cell.

    The second input to this hypothesis is knowledge that ME/CFS involves low thresholds for going into anaerobic metabolism, which drop even lower following exercise. What I'm guessing now is that those of us who are vulnerable to this disease carry some mitochondrial genomes which are adapted to low oxygen conditions. During health these are a small minority of all our mitochondria, but if some pathological process causes us to spend much time above anaerobic threshold, clonal expansion of those mitochondria best adapted to this condition increases their numbers, at least in those tissues affected by exercise or ischemia. (Hypoperfusion may result in localized hypoxia.) There is already considerable research literature on reperfusion injury associated with such dramatic changes as stroke, but less is known about the kind of episodic ischemia or cellular hypoxia we experience.

    I'm suggesting the population of mitochondria in our cells shifts to adapt to chronic cellular hypoxia via clonal expansion of some minor variant mitochondrial genome. I'm not sure how much change is required, but it would take little to trigger some kind of immune response when there is confusion about invasion of microbes from the gut or lungs with similar biochemical properties.

    This brings to mind a very strange response I believe Dr. Paul Cheney discovered in measurements of cardiac function in ME/CFS patients. It involves IVRT (isovolemic relaxation time) which is a good proxy for direct measurements showing diastolic dysfunction in the left ventricle. What I think he said was that all his patients showed a peculiar change in IVRT when they held their breath. This would be direct evidence of an unusual response to limited hypoxia in heart muscles.

    I can't find this in publication. Does anyone else recall exactly what that peculiar response was?
     
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  7. lansbergen

    lansbergen Senior Member

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    I believe in nature. Nature will try to do what is needed in a situation by trial; and error. That can be multiply the mitochondria that are best suited for the situation at hand. When the crisis is over it probably will go back to the normal situation.
     
  8. anciendaze

    anciendaze Senior Member

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    In many cases nature will return to the status quo ante, but not in all. If the population of mitochondria has shifted in the direction of anaerobic metabolism, and the patient now has an unusually low anaerobic threshold, repeatedly pushing beyond the envelope of aerobic metabolism, as most of us do at first, will cause the mitochondria suited to low oxygen levels to persist.

    There is another aspect which I was trying to explore earlier. Serious ischemia can lead to sterile cell death. This doesn't necessarily remain sterile. I'm thinking now of my own experience with hernias. A strangulated hernia causes ischemia, and the result is often gangrene. Anaerobic pathogens are particularly lethal, and this is a situation which will cause immune response to pull out all the stops. More limited ischemia in diabetes or even Raynaud's phenomenon can also lead to gangrene is the worst cases. What is the trigger point for massive immune response? How close can episodic ischemia come to allowing anaerobic pathogens in before some particular response is invoked?

    There is a substantial immune response going on when we are infected with an actual flu-like pathogen. Can anyone tell me why this results in the symptoms of flu? Why, for example, do muscles ache when the pathogens are in the lungs or gut?

    Immune systems are very good at amplifying tiny signals into massive responses. Just because the triggering mitochondria are in the minority does not mean the response will always be proportionate.

    A second problem is that patients are never completely free of pathogens. We keep adding to the list of "benign" microbial infections which are "mostly harmless" -- except when they cause cancer or a wide range of diseases. Just considering what the herpes viruses commonly found in humans will do in the circumstances described above is a reasonable topic for research.
     
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  9. lansbergen

    lansbergen Senior Member

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    Sickness response.
     
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  10. lansbergen

    lansbergen Senior Member

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    Does not exclude it is possible to return to normal when the causing pathogen is beated or the patient does not overdo.

    Remember I said I was dying? I would have if I had not started to help nature to fight the infection.
     
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  11. anciendaze

    anciendaze Senior Member

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    And how do you tell if you are above a very low anaerobic threshold? I haven't found any good way to tell prior to overdoing it, and paying a price.
    Sorry, I didn't catch that.

    There is a point here concerning a response that may or may not be counted as immune. We tend to think of the immune system as B-cells and T-cells, but overlook intracellular mechanisms that deal with foreign or misfolded proteins. When we get into details of such responses we find a plethora of terms like zinc fingers, RING ("Really Interesting New Gene") and ligands involved in recognizing and marking the offending proteins for disposal. Marking these involves attaching ATP molecules, which then go on to power the molecular machinery which degrades the offending molecule. These ATP molecules are not available for other normal cellular purposes.

    There are multiple lines of evidence indicating that ME/CFS patients are experiencing a diversion of cellular resources into this activity. There is also evidence we experience slow clearing of metabolic waste products, again likely because the machinery is busy doing something else. At this point I can't rule out the existence of real pathogens, but I have to say they must be either hard to find or misidentified as harmless. I have wondered about cellular mechanisms misidentifying normal proteins needed for healthy metabolism as defective. If mitochondrial genomes were uniform this would have a devastating effect that would probably kill patients. Learning that even healthy people have multiple mitochondrial genomes changes the picture dramatically.

    Biological defenses are far from perfect, and it is only too easy for the low-level mechanisms involved to match the wrong molecules. In some cases this results in autoimmune disease, though even in those cases there is no exact match between autoantibody levels and clinical disease. Something more is going on which we have not pinned down. In other cases a failed match allows cancer to proliferate. I've been looking for things that degrade precisely targeted responses.

    If multiple mitochondrial genomes are present in everybody, we have a excellent chance of triggering a false match when some unrelated pathological process changes the population via clonal expansion of a rare variant. Remember that evidence of clonal expansion of pathogens is a trigger for immune response against them. Immune systems will tolerate quite a range of potentially harmful organisms as long as they don't begin increasing exponentially.
     
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  12. lansbergen

    lansbergen Senior Member

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    Not easy but I learned. Not saying I do not make mistakes anymore. Of course I stiill sin but I notice much sooner when I do.
     
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  13. lansbergen

    lansbergen Senior Member

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    Yes, it is very complicated.
     
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  14. lansbergen

    lansbergen Senior Member

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    Yep
     
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  15. anciendaze

    anciendaze Senior Member

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    Hope people will bear with me if I repeat a request which may have become lost in the shuffle. I recall Dr. Paul Cheney saying he had found a sign which showed up in 100% of his CFS patients when he did echocardiograms. It involved a heart measurement called IVRT, and changed in a peculiar way when patients held their breath, indicating a novel response to hypoxia. I'm now interested in reconsidering that in light of a possible shift in predominant mitochondrial genomes due to a triggering illness.

    I have not found this in publications. Can anyone supply more information?
     
  16. lansbergen

    lansbergen Senior Member

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    I have not followed Cheney but several on here did.

    Did any of you save what anciendaze is looking for now?
     
  17. Snowdrop

    Snowdrop Rebel without a biscuit

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  18. anciendaze

    anciendaze Senior Member

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    No, that is quite a different idea that Cheney has tried. He has tried lots of things. I'm specifically looking for mention of changes in isovolemic relaxation time (IVRT) in response to mild hypoxia. I'm sure he has said that 100% of his CFS patients exhibit a peculiar sign during echocardiograms, but I did not follow up when I heard this. This seems to be his unique observation, to which I would not give much weight if he had not done more echocardiograms on ME/CFS patients than anyone else. (I believe the numbers are up in the thousands.) This is also not something in a standard exam by a cardiologist.
     
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  19. Little Bluestem

    Little Bluestem All Good Things Must Come to an End

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    How about an anaerobic threshold test and a heart rate monitor?
     
  20. anciendaze

    anciendaze Senior Member

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    That would be fine, if the threshold did not change. The problem is that the whole purpose of conditioning is to change the threshold. You would have to keep testing for a new anaerobic threshold each time you exercised. We are all also very much aware that other factors, like a passing minor illness, can cause thresholds to drop.

    For healthy people exercising with a heart rate monitor works very well. They have a much broader target range to hit in a workout. I was doing this many years ago, before you could see people wearing a Fitbit. With my current problem my heart rate moves close to anaerobic threshold when I climb a flight of stairs in my townhouse between the kitchen and the bedroom. Eating breakfast, bathing and changing clothes is a workout. So is doing laundry. This has not been adequate to improve my condition. People who insist we only need more exercise refuse to believe anyone could have such difficulties unless they were patients with heart failure. We may have performance in the same range, but we do not have heart failure by the standards cardiologists use.
     
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