Universal heteroplasmy of human mitochondrial DNA

[anciendaze]

I've now found the source of that talk by Paul Cheney I recalled. It was a talk delivered to the Irish ME association. Here's a direct link to the YouTube video of the slides.

The original sign was an increase in IVRT when patients were given oxygen. They got worse. The later version of test simply as asks patients undergoing the echocardiogram to hold their breath for 30 seconds after exhalation, which causes IVRT to decrease. This is a paradoxical response exactly opposite to that of healthy people like the mountaineers he discusses. The cause has not been pinned down.

This looks like very clear evidence of a seriously dysfunctional energy metabolism. At this point nobody knows if populations of mitochondria are different in ME/CFS patients in the way hypothesized earlier in this thread.

 

[Richard7]

@anciendaze

This is something I wonder about from time to time. I see a physio who is in favour of buteyko. A method named after the person who came up with it for returning those with disordered over-breathing to normal.

The idea, as I remember it, is that while overbreathing you end up with too low a concentration of CO2 in your lungs, which reduces the O2 concentration in the blood. A symptom of this is muscles with a harder firmer tone.

My phisio was aware of breathing being an issue with me from when I started seeing her in 2003. I had hard muscles and was overinflating my chest in an attempt to sit up. (Think of the way people take in and hold a breath when they are lifting something heavy, only do it all day.)

In 2009, I tried buteyko (shortly after she became interested in it) and found that it seemed ok at first but I did not get very far before it started leading to increased anxiety.

Maybe anxiety is not the word, I know last year I described it as feeling like the floor had fallen away and I was plunged into a cold clinical and dark mood that lasted for hours even though I had stopped buteyko immediately.

I found I got into the same state when I tried meditating and got into a trance state, well dipped my toes in one - that water was way too cold!

Both buteyko and body scan meditation certainly led to softer muscles and changes in breathing.

I also found something similar happened when I tried fredd's protocol late last year.

I seem however to need the harder muscles and overbreathing to deal with POTS. When I was mediatating and later doing the methylation protocol I had big issues with lightheadedness, heart rate around 110-130bpm on standing, 44 - 47 at rest. (I am less certain about the upper measurement It is hard to get a good reading when you are lightheaded, so I did not measure when I was at my very worst and have never tried standing for 10 minutes for such a test.)

Looking at the heart rate pattern on the O2 perfusion meter that I use for testing my heart rate, it looks nothing like cheney's pattern. But I do not know if it is accurate. My O2 perfusion is usually low, sometimes under 90, gererally in the low 90s, but 96-99 when on freddd's protocol.

So the idea that the low O2 perfusion is something that we need seems to work, but I do not know where this leads us.

It does however make sense that this could lead to different mitochondria flourishing in the new ecosystem, which would probably make switching back more difficult if almost all of our mitochondria were now of a kind that does not work in a cell with more oxygen.

Maybe Cheney should have done the experiment on people who live at those high altitudes, or we should look at a comparison between their mitochondria and our own.

This is something I often wonder about with the gut microbiome. We know that exercise changes the the gut microbiome, which is usually presented as a reason for doing more exercise (in a healthy population). But the corollary is probably that we have a microbiome that favours inactivity. I know that I seem to get diarrhoea when I do more physical activity.

 

[anciendaze]

@Richard7

Holding breath was simply a diagnostic test, not really a therapy. Hyperventilation is a problem with some POTS patients, and you seem to be in that category. In some cases patients are better when breathing is slightly restricted. I recall reading about measurements which normalized while breathing through a short length of garden hose -- not usually a practical treatment option. Feelings of suffocation induce panic attacks, which may be treated by controlling breathing better. I'd also point out that ME/CFS patients have high lactate levels, and injections of lactate were once shown to induce panic attacks. (Back when nobody asked if that research was ethical.) This can predispose patients to hyperventilation.

I don't know what is going on with mitochondria, I am simply speculating about the mystifying results of studies on mitochondria. This topic shows that we have been operating with serious misconceptions when we try to measure what the little buggers are doing.

I'm also wondering if multiple mitochondrial genomes create a greater risk of autoimmune responses. Those oxidative reactions which are commonly considered bad can serve a definite purpose in disposing of misfolded or foreign proteins. It is possible the problem comes from misidentifying healthy molecules as defective.

What you have said about your own case points to real orthostatic intolerance and dysautonomia. If you can get a knowledgeable doctor to address those issues it may improve other symptoms.

Normal autonomic response to exercise diverts circulation in predictable ways. One of these is to reduce blood flow to the gut, pausing digestion, while the flight-or-fight response is active. Excessive transient ischemia in the gut can produce exactly the problems you describe. Treating gut flora without changing the ischemia will predictably return to a dysfunctional state later as the sequence of events repeats. Treating the ischemia may make it possible to successfully restore gut function with probiotics.

 

[green_monster]

Ron Davis/Open Medicine has a new member join the Scientific Advisory Board - Dr. Robert K. Naviaux, MD, PhD.

http://www.openmedicinefoundation.org/2016/02/10/welcome-dr-naviaux-to-our-team/

"Dr. Naviaux runs the Robert Naviaux Laboratory at UC San Diego, which is doing genetic research into mitochondrial dysfunctions. He is founder and co-director of the Mitochondrial and Metabolic Disease Center at UCSD. Additionally, he is the co-founder and a former president of the Mitochondrial Medicine Society, and a founding associate editor of the journal Mitochondrion."

 

[MeSci]

This is something I often wonder about with the gut microbiome. We know that exercise changes the the gut microbiome, which is usually presented as a reason for doing more exercise (in a healthy population). But the corollary is probably that we have a microbiome that favours inactivity. I know that I seem to get diarrhoea when I do more physical activity.

Exertion increases gut permeability. This thread discusses it in ME/CFS, but it is also seen in healthy people:

http://jap.physiology.org/content/82/2/571.full

I wonder what @Jonathan Edwards thinks about the implications of the heteroplasmy of human mtDNA (if any)?

 

[lansbergen]

SOD2 dislocation and depletion is associated with the infection I suspect. I think the infection must be brought back to low enough levels to get to the point autophagy and other cellmachinery can control the infection load.

 

[Jonathan Edwards]

Exertion increases gut permeability. This thread discusses it in ME/CFS, but it is also seen in healthy people:

http://jap.physiology.org/content/82/2/571.full

I wonder what @Jonathan Edwards thinks about the implications of the heteroplasmy of human mtDNA (if any)?

I think we have known about this sort of thing for a while. Mitochondrial DNA follows a different pattern of inheritance because it does not get reshuffled the way chromosome DNA does. Its odd behaviour can explain some rare progressive diseases but I am not clear that it has a big role in common conditions.

 

[MeSci]

I think we have known about this sort of thing for a while. Mitochondrial DNA follows a different pattern of inheritance because it does not get reshuffled the way chromosome DNA does. Its odd behaviour can explain some rare progressive diseases but I am not clear that it has a big role in common conditions.

Do you include ME/CFS amongst common conditions?

 

[Jonathan Edwards]

Do you include ME/CFS amongst common conditions?

Maybe, maybe not all forms - dunno!

 

[Little Bluestem]

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.

I don't think anyone here uses a heart rate monitor for conditioning or to improve their condition. Instead it is used to try to avoid going over a very low anaerobic threshold and not make their condition worse. The fact that the threshold changes does make this less than perfect.

 

[anciendaze]

My point in starting this topic was not that this is "the answer" (tm) for ME/CFS, it was my shock at discovering part of the factual bedrock concerning mitochondria long taught in medical schools was simply wrong. The absence of crossover Prof. Edwards mentions was assumed to mean human cells generally exhibited mitochondrial homoplasmy, that except for rare mutations, and extremely rare discovery of paternal mtDNA, all mitochondria in an individual had the same genome.

This also implied that you would find the same mitochondrial genes in all tissues, which meant you could investigate mitochondrial genes in some convenient place like blood, and ignore differences in muscles. This was a good thing because nobody wants to do biopsies of heart muscle without an excellent reason. If there are multiple variants in everyone so far tested carefully, and different proportions of these varieties appear in different tissues, you can't assume changes in mitochondrial phenotype are due to mutation. They could simply be the result of clonal expansion of mitochondria you had overlooked.

This greatly complicates research on them, and might explain why there are virtually no solid examples in the literature of any changes in mitochondria due to environmental factors.

 

[Richard7]

Yeah fascinating. I really want to understand all of this stuff, but I have just come off a month or so of bad pots and am at best only at the edge of understanding this stuff. I suspect that I am really like someone looking at stars and seeing patterns that no sensible person would draw - Orion swinging a club, yeah sure.

My though above was that the thing that I remembered from that cheney talk was his idea that favouring anearobic of aerobic being a protective measure. And that increasing O2 made things worse was evidence of this.

My thought was that this tied into the buteyko, which should have the same effect as increasing O2, leading to adverse effects.

I know that the low O2 also stimulates AMPK so it would be stimulating the growth of mitochondria. which would presumably lead to the clonal expansion of whichever mitochondria survive best in a cell that is not really doing much aerobic respiration which would not be mitochondria that are much use to us I guess.

anyway, sorry if I am to vague and ignorant to offer much to the discussion.

 

[Marco]

@anciendaze

In the scenario you're outlining it seems to me that you should be able to find some physiological correlate such as a switching in muscle fibre type. As previously discussed :

http://forums.phoenixrising.me/inde...f-muscle-fibres-from-patients-with-cfs.11860/

 

[anciendaze]

@anciendaze

In the scenario you're outlining it seems to me that you should be able to find some physiological correlate such as a switching in muscle fibre type. As previously discussed :

http://forums.phoenixrising.me/inde...f-muscle-fibres-from-patients-with-cfs.11860/

That's right, but this complication means it would not be nearly as simple to validate as previously imagined. That, in turn, would help explain the utter confusion on the entire subject of acquired mitochondrial problems.

What I actually suspect is even less obvious, and crosses boundaries between medical fields.

Paul Cheney has been a stimulating source of ideas, but I do not agree with some of his conclusions. (I think it should go without saying that he does not have any special skills in the politics of medicine, the source of most actual changes in practice.) He is right, as far as it goes, in a great deal of what he says about defects in oxygen metabolism and energy production. What I suspect is that he is using logic which makes sense in dealing with human artifacts, but is frequently invalid in biology.

Scarcely anything in biology only serves a single function. Evolution is supremely opportunistic, and has the habit of reusing mechanisms produced for entirely different functions. The association of oxidative stress with reperfusion injury got me thinking about why evolution has not eliminated such damaging characteristics. I decided this was an extension of immune response, typically used to destroy misfolded or foreign proteins by attaching ATP molecules to the offending proteins to mark them and power degradation. I'm not very concerned about artificial boundaries between subjects introduced by humans who understood a great deal less than is now known. If this doesn't fit in with models of B-cells and T-cells, etc. we will just need new models. (Frankly, I'm still waiting for anyone to view immune systems as actual systems, not just collections of disparate components.)

Cheney is adamant that the problem is really a heart/energy problem, not an autonomic problem. I think this has blinded him to a role for autonomic systems quite different from the one envisioned by most specialists in autonomic neurology. Dysfunctional autonomic responses frequently exaggerate the natural reduction in blood flow to extremities and gut during exercise. This leads to a temporary increase in bacterial translocation, even if immune response prevents the condition from becoming sepsis. If I start thinking of oxidative problems due to reperfusion as a kind of immune response to a very dangerous challenge from anaerobic organisms, though often misdirected, things begin to make sense. After severe hypoperfusion the body doesn't wait to identify specific pathogens, it produces an overwhelming response you might call "going nuclear".

In special cases, like the production of anticardiolipin antibodies (ACA) we see a direct link between immune response to microbes and energy production. I'm guessing there are a lot more such mechanisms than have been identified, simply because we are dealing with potentially very dangerous infections and fundamental cellular energy production.

From a treatment standpoint what this would say is that those episodes of hypoperfusion in the gut repeatedly trigger some kind of response, even if we currently don't call it immune, against molecules involved in mitochondrial metabolism. If you don't deal with the autonomic problems, you won't stop the recurrence of energy dysfunction.

This sequence of ideas does not depend on dramatic changes in mitochondrial genetics, though more complicated genetics would increase the likelihood of misdirected response. That was just the trigger that caused me to reevaluate what I thought I knew.

The pattern of reasoning here was a matter of looking for cyclic cause and effect. Reasoning about progressive diseases is easier because if you wait long enough there will be problems that are easy to find, perhaps at autopsy. You can reach conclusions with linear chains of cause and effect. This has caused us to misread a great deal of biological control as some kind of crude setpoint control system because we have learned from dealing with seriously broken control systems. I'm not certain anything I've seen is an actual example of such crude biological control in healthy individuals. If there is such, I'm interested in finding out how the set point is calibrated, because this is a real problem in engineering control systems.

(Anecdote: "Why isn't this liquid oxygen sensor giving correct readings?" "Because it isn't a liquid oxygen sensor. It was calibrated in liquid nitrogen.")

When dealing with chronic diseases you need to think in terms of cyclic cause and effect, and a major portion of the cycle is missing from Cheney's model. I'm guessing the missing links are off in a different medical field where people don't talk to the ones aware of defects in energy production, etc. There is a lot on noncommunication in medicine, and not just at the level of doctors and patients.

 

[Marco]

Toll like receptors are notoriously promiscuous and the immune system, particularly in the CNS, doesn't appear to discriminate between danger signals due to infection, physiological stress or psychological stress in mounting an immune response.

The 2 day CPET results are interesting. I have a working model that attributes the decrement in performance on day two to sympathetic ANS overactivaton reducing the ventilatory/anaerobic threshold with downstream effects on cardiovascular function, reduced cerebral (and peripheral) blood flow, endothelial function, arterial stiffness etc. I'm not ruling it out but no need to invoke bacterial translocation.

 

[lansbergen]

Anybody thought of mitochrondria might still act in some aspects as their ancestors did?

 

[anciendaze]

@Marco,

The 2CPET results match other indications of slow clearance of lactate. This indicates to me that something more than autonomic function is changing. I'm not suggesting there is a great deal of bacterial translocation, as happens in actual diseases with flu-like symptoms, I'm suggesting the body is primed to overreact. This looks like a case where the response is much stronger than the cause would normally suggest, which brings to mind the remarkable extent to which immune systems amplify tiny signals from pathogens, and remember previous encounters.

 

[Marco]

@Marco,

The 2CPET results match other indications of slow clearance of lactate. This indicates to me that something more than autonomic function is changing. I'm not suggesting there is a great deal of bacterial translocation, as happens in actual diseases with flu-like symptoms, I'm suggesting the body is primed to overreact. This looks like a case where the response is much stronger than the cause would normally suggest, which brings to mind the remarkable extent to which immune systems amplify tiny signals from pathogens, and remember previous encounters.

I'll send you a message tomorrow. I feel we're thinking along similar lines.

 

[anciendaze]

Here's one kind of pathogen I'm thinking might cause a misdirected response against mitochondria, Rickettsia. I would doubt most of us could harbor an active infection for long, some are quite lethal. (Rocky Mountain spotted fever is 70% lethal if untreated.) This would however justify evolution of a very strong immune response, even if this response were damaging in other contexts. A range of such pathogens exist in many environments, and even where they are not present it is very likely humans will react strongly to anything which resembles them. Multiple mitochondrial genomes would naturally raise the probability of a misdirected response.

Here's a quote to show why I feel this is a reasonable cause for damage to mitochondria:

Certain segments of rickettsial genomes resemble those of mitochondria.[17] The deciphered genome of R. prowazekii is 1,111,523 bp long and contains 834 genes.[18] Unlike free-living bacteria, it contains no genes for anaerobic glycolysis or genes involved in the biosynthesis and regulation of amino acids and nucleosides. In this regard, it is similar to mitochondrial genomes; in both cases, nuclear (host) resources are used.

ATP production in Rickettsia is the same as that in mitochondria. In fact, of all the microbes known, the Rickettsia is probably the closest relative (in a phylogenetic sense) to the mitochondria. Unlike the latter, the genome of R. prowazekii, however, contains a complete set of genes encoding for the tricarboxylic acid cycle and the respiratory chain complex. Still, the genomes of the Rickettsia, as well as the mitochondria, are frequently said to be "small, highly derived products of several types of reductive evolution"

 

[merylg]

I just came across this & thought it explains things mitochondrial in a way that's easy to understand...
http://www.vmpgenetics.com/resources/dr-fran-kendall-factoid-fridays/its-all-genes/