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Mitochondrial and Energy Metabolism Dysfunction in ME/CFS — Myhill, Booth and McLaren-Howard Papers
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I question the simple hypothesis that 'low ATP production = ME/CFS symptoms'. To me it's not as simple as not enough energy getting to the body's cells. If that were so, I shouldn't be able to go for a 3 hr bike ride or hike through the woods, or shovelling soil: all things that I have done. I've suffered PEM 24 hrs later, but I'm pretty sure that I could have done those things the following day if I really needed to. I don't feel that my ME/CFS has decreased my physical energy limits significantly, which I think it would have if it was simply a global x% reduction in ATP production/transport.
I accept that mitochondrial dysfunction is part of the disorder, but I think what it's doing is shifting the levels of one or more specific biochemical processes, with the result of that feeding back to maintain the mito dysfunction, probably through the immune system. When I started reading this thread yesterday, I had the sudden question: 'do t-cells have mitochondria?' Yes they do, and the t-memory cells and t-effector cells have different mitochondrial arrangements and fuel sources (t-eff cells use fatty acids).
I think that many of the symptoms I feel arise from kynurenine imbalance. I get the same increase in symptom severity from exercise or viral infections, both of which activate t-cells and increase IFN-g levels and thus kynurenines. The severity also correlated with tryptophan transport into my brain (increasing KYN); it wasn't affected by supplemental 5-HTP, which is the other, non-kynurenine pathway for TRP. My symptoms seem--from what I've read--consistent with excess kynurenines, particularly quinolinic and picolinic acid. A cytokine profile showed excess MIP-alpha and beta, which seems consistent with excess picolinic acid.
The defects in mitochondrial function might cause excess superoxide and peroxynitrite levels, which would affect kynurenine production. It would also explain why antioxidants and peroxynitrite scavengers increase the severity of my symptoms.
I also had a significant increase in symptom severity when I ate animal fats (I assume it's the palmitic acid) unless I took supplemental carnitine, which transports the fatty acids across the mitochondrial membrane. I wondered why having extra palmitic acid in the microglial (or maybe t-eff) cells (due to lack of transport into the mitochondria) would increase symptoms. Still wondering about that one...
Any thoughts on this by someone with a better knowledge of cell function? Is there an obvious flaw in my reasoning?
I accept that mitochondrial dysfunction is part of the disorder, but I think what it's doing is shifting the levels of one or more specific biochemical processes, with the result of that feeding back to maintain the mito dysfunction, probably through the immune system. When I started reading this thread yesterday, I had the sudden question: 'do t-cells have mitochondria?' Yes they do, and the t-memory cells and t-effector cells have different mitochondrial arrangements and fuel sources (t-eff cells use fatty acids).
I think that many of the symptoms I feel arise from kynurenine imbalance. I get the same increase in symptom severity from exercise or viral infections, both of which activate t-cells and increase IFN-g levels and thus kynurenines. The severity also correlated with tryptophan transport into my brain (increasing KYN); it wasn't affected by supplemental 5-HTP, which is the other, non-kynurenine pathway for TRP. My symptoms seem--from what I've read--consistent with excess kynurenines, particularly quinolinic and picolinic acid. A cytokine profile showed excess MIP-alpha and beta, which seems consistent with excess picolinic acid.
The defects in mitochondrial function might cause excess superoxide and peroxynitrite levels, which would affect kynurenine production. It would also explain why antioxidants and peroxynitrite scavengers increase the severity of my symptoms.
I also had a significant increase in symptom severity when I ate animal fats (I assume it's the palmitic acid) unless I took supplemental carnitine, which transports the fatty acids across the mitochondrial membrane. I wondered why having extra palmitic acid in the microglial (or maybe t-eff) cells (due to lack of transport into the mitochondria) would increase symptoms. Still wondering about that one...
Any thoughts on this by someone with a better knowledge of cell function? Is there an obvious flaw in my reasoning?
If you can go for a 3 hour bike ride, you probably have mild ME/CFS. But if you were a severe ME/CFS patient, you'd typically find even a 10 minute walk would cause a crash/PEM. And in very severe patients, a 5 meter walk from their bed to the bathroom is enough to cause PEM.
When you look at the severe end of the ME/CFS spectrum, it does start to seem that there could be some energy production deficit.
When you look at the severe end of the ME/CFS spectrum, it does start to seem that there could be some energy production deficit.
Pretty confident. I used to think this was some really rare chronic neuroinflammation. I thought that the 'feel worse 24 hrs after activity' was simply due to IFN-g, which certainly fits; I hadn't encountered the term 'PEM'. Whenever I looked into CFS, I didn't seem to have four of the eight criteria, but that was the American criteria, which seems designed to prevent people from qualifying for insurance payouts. Then I checked the Canadian criteria, and the new international criteria, and realized that I did fit. Reading in this forum firmed up my confidence. I haven't bothered to try to get a clinical diagnosis, because it would require a lot of effort and not result in any treatment.
Hip's response made me realize that I haven't come across a clear definition of the different levels of ME/CFS.
Patients with severe limits to physical effort don't invalidate my hypothesis, I think. The physical effects of greatly reduced ATP levels would just be a stronger side-effect. It would still be something in the immune system keeping the mitochondria in the abnormal state. I don't think it's a drastic increase in a cytokine, since that would most likely have shown up in tests. I think it's more likely an abnormal response to a mild increase.
For those of you who have had viral infections since developing ME/CFS: does having an infection increase the same symptoms that you normally feel? It certainly does for me, though I've only had viral infections a few times since developing ME/CFS.
Hip's response made me realize that I haven't come across a clear definition of the different levels of ME/CFS.
Patients with severe limits to physical effort don't invalidate my hypothesis, I think. The physical effects of greatly reduced ATP levels would just be a stronger side-effect. It would still be something in the immune system keeping the mitochondria in the abnormal state. I don't think it's a drastic increase in a cytokine, since that would most likely have shown up in tests. I think it's more likely an abnormal response to a mild increase.
For those of you who have had viral infections since developing ME/CFS: does having an infection increase the same symptoms that you normally feel? It certainly does for me, though I've only had viral infections a few times since developing ME/CFS.
How hard did you ride or hike?
When you experienced PEM as noted above how long did it last?
When you experienced PEM as noted above how long did it last?
Yes, I'm sitting here now drinking coffee and eating a nut bar, with magnesium malate to follow.
Those scales may be useful for claiming disability benefits but they're quite variable and do nothing to get to the heart of what's wrong with people or how to fix them.
Reading through all the descriptions Hip provided, I generally fall between 60 and 70, yet on others I was mild and on others moderate. I work 0-4 hours 3 days a week, get medical treatment 2 days a week, care for myself, do no housework, sleep a lot during the day and have disturbed sleep at night...
Those descriptions are useless to me...and the disability people are still trying to figure out how to get me to work a 40 hour week. I'm not mild...
Not sure there is a good one as I noted above.
From everything I've seen on the forum, as well as going to the OMF Symposium and talking directly to researchers there, it seems that while we may share symptoms, there are some subsets of us, with discrete drivers of our illness, with significant comorbidities in many cases.
Our mitochondria are definitely upset about something, and if one goes down Naviaux's categories of cell dangers, its quite likely that a few or more are affecting each of us. The problem is that the conventional medicine system is not good at testing for impacts of these or doing anything about most of them.
It seems pretty clear that our immune systems are dysfunctional - some are underactive, maybe not fighting off hidden infections, while others are overactive, with autoimmune disease and auto-antibodies. Again, most doctors won't think to look for or find them. (I had a rheumatologist fire me as she didn't know what was wrong, when the next doctor I saw found 4 types of autoimmune problems she'd missed.)
Its unlikely many of us can get well without proper diagnosis and appropriate treatment to remove the cell dangers, fix the immune system, and repair collateral damage to cell and mitochondrial membranes, organs, and depleted biochemical processes.
I'm skeptical that there's a magic pill that's going to fix all of us. One may help a great deal, but it will still be a matter of addressing these other issues to avoid relapse.
Quite likely. My ME/CFS doctor explained to me, and I heard it again at the Symposium, that infections can push the immune system into a reactive state by creating auto-antibodies, many times inappropriately, through molecular mimicry - trying to make antibodies to what we have but mistakenly building something bad instead.
I do not get as sick as I should. No to low fever, swollen lymph nodes, stuffed up sinuses and ears, and then there's the fatigue... even when I caught a cold.
My immune system is underreacting to them. I recently had IVIG for the first time, which did make me sick, though...
Reading through all the descriptions Hip provided, I generally fall between 60 and 70, yet on others I was mild and on others moderate. I work 0-4 hours 3 days a week, get medical treatment 2 days a week, care for myself, do no housework, sleep a lot during the day and have disturbed sleep at night...
Those descriptions are useless to me...and the disability people are still trying to figure out how to get me to work a 40 hour week. I'm not mild...
Not sure there is a good one as I noted above.
From everything I've seen on the forum, as well as going to the OMF Symposium and talking directly to researchers there, it seems that while we may share symptoms, there are some subsets of us, with discrete drivers of our illness, with significant comorbidities in many cases.
Our mitochondria are definitely upset about something, and if one goes down Naviaux's categories of cell dangers, its quite likely that a few or more are affecting each of us. The problem is that the conventional medicine system is not good at testing for impacts of these or doing anything about most of them.
It seems pretty clear that our immune systems are dysfunctional - some are underactive, maybe not fighting off hidden infections, while others are overactive, with autoimmune disease and auto-antibodies. Again, most doctors won't think to look for or find them. (I had a rheumatologist fire me as she didn't know what was wrong, when the next doctor I saw found 4 types of autoimmune problems she'd missed.)
Its unlikely many of us can get well without proper diagnosis and appropriate treatment to remove the cell dangers, fix the immune system, and repair collateral damage to cell and mitochondrial membranes, organs, and depleted biochemical processes.
I'm skeptical that there's a magic pill that's going to fix all of us. One may help a great deal, but it will still be a matter of addressing these other issues to avoid relapse.
Quite likely. My ME/CFS doctor explained to me, and I heard it again at the Symposium, that infections can push the immune system into a reactive state by creating auto-antibodies, many times inappropriately, through molecular mimicry - trying to make antibodies to what we have but mistakenly building something bad instead.
I do not get as sick as I should. No to low fever, swollen lymph nodes, stuffed up sinuses and ears, and then there's the fatigue... even when I caught a cold.
My immune system is underreacting to them. I recently had IVIG for the first time, which did make me sick, though...
That's a bit of a strange thing to day. Scales of illness severity are not supposed to explain what causes a disease, nor how to treat it; they are just designed to gauge how severe an illness is. There are several different ME/CFS scales available, and such scales are useful when assessing the efficacy of a treatment in studies (by comparing your starting point and ending point after treatment on an ME/CFS scale, you can gauge the efficacy of a treatment).
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I have the same issue with under-reacting to colds and flus. I have had dozens in the last 10 years, yet not one fever. A sure sign of a weak innate immune system.
I remember reading here at PR about someone that fairly recently recovered from cfs. They were talking about how thrilled they were when they got sick after recovering AND got their first fever in years!
I wonder how much of a role mitochondrial dysfunction might play in a weak immune system? Low energy, from dysfunctional mitochondria in immune cells, could make them weak and less able to defend against viruses and bacteria.
Jim
I remember reading here at PR about someone that fairly recently recovered from cfs. They were talking about how thrilled they were when they got sick after recovering AND got their first fever in years!
I wonder how much of a role mitochondrial dysfunction might play in a weak immune system? Low energy, from dysfunctional mitochondria in immune cells, could make them weak and less able to defend against viruses and bacteria.
Jim
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I am in the same case. It was a professionnal intermittent exposure to organophosphate from 1996 to 2002.
I had already some symptoms before exposure, but my bigger crash was 2002.
From 1992 to 1997, I was also exposed professionally and regularly to formaldehyde inhalations, which have shown to produce mitochondria dysfunction...
https://www.ncbi.nlm.nih.gov/pubmed/26728267
Both the organophosphate and formaldehyde products I was using at that time are now confirmed carcinogens and were totally prohibited around 2002.
Do you know if there would be a way to prove the exposure is responsible for our mitochondria dysfunction?
I had already some symptoms before exposure, but my bigger crash was 2002.
From 1992 to 1997, I was also exposed professionally and regularly to formaldehyde inhalations, which have shown to produce mitochondria dysfunction...
https://www.ncbi.nlm.nih.gov/pubmed/26728267
Both the organophosphate and formaldehyde products I was using at that time are now confirmed carcinogens and were totally prohibited around 2002.
Do you know if there would be a way to prove the exposure is responsible for our mitochondria dysfunction?
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You mean legally prove, or scientifically prove? I don't know that much about it, but I would not have thought you could scientifically prove this in an individual case, because the argument might be that the damage could come from some other cause. However, I guess it is conceivable that you might legally prove it, if you had a test that showed mitochondria DNA damage.
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I suppose that mitochondria permanent damage from OrganoP exposure may happen only after a drastic exposure, but what about chronic exposure (from food products or from pets treatments). Does it cause permanent damage as well or can the mitochondria go back to normal after the pesticide is clear out of the body.
Many people speak about detox from heavy metals, but what can we do to detox pesticids like organoP and Pyrethroids?
I wouldn't be surprised if people with CFS/ME or Fibromyalgia had more polymorphisms in the Mitochondrial DNA than control.
This could be an explanation to the adult onset for these disease, and to a specific sensitivity to the environmental factors altering the mitochondria function, whatever the factor (chemical/autoimmun/heavy metal/...)
My grand-mother was ill like I am, my mother was less affected (only after 50), and my aunts were fine...So I suppose something in our mito DNA induces a weakness that appears only in a stressful environment.
Many people speak about detox from heavy metals, but what can we do to detox pesticids like organoP and Pyrethroids?
I wouldn't be surprised if people with CFS/ME or Fibromyalgia had more polymorphisms in the Mitochondrial DNA than control.
This could be an explanation to the adult onset for these disease, and to a specific sensitivity to the environmental factors altering the mitochondria function, whatever the factor (chemical/autoimmun/heavy metal/...)
My grand-mother was ill like I am, my mother was less affected (only after 50), and my aunts were fine...So I suppose something in our mito DNA induces a weakness that appears only in a stressful environment.
Regularly using over a period of many years organophosphate pesticides indoors to spray houseplants has been linked to diseases such as Parkinson's, which itself is linked to mitochondrial DNA damage. More info here.
Mitochondria are constantly being rebuilt and replaced in the cell (the lifespan of a mitochondrion is in the order of days or weeks). However, since mitochondria are the only organelle to carry their own DNA, any DNA damage to mitochondria will propagate down into the new generations of mitochondria.
Unlike the organochlorines they were designed to replace, organophosphates do not accumulate in the body (that's why they are considered safer than organochlorines, which have now been phased out due to their bioaccumulative properties). Synthetic pyrethroids don't accumulate either.
Mitochondria are constantly being rebuilt and replaced in the cell (the lifespan of a mitochondrion is in the order of days or weeks). However, since mitochondria are the only organelle to carry their own DNA, any DNA damage to mitochondria will propagate down into the new generations of mitochondria.
Unlike the organochlorines they were designed to replace, organophosphates do not accumulate in the body (that's why they are considered safer than organochlorines, which have now been phased out due to their bioaccumulative properties). Synthetic pyrethroids don't accumulate either.
Pyrethroids accumulate in rats, fish, and are known to affect the brain:
https://academic.oup.com/toxsci/art...cticides-Directly-Activate?redirectedFrom=PDF
https://www.ncbi.nlm.nih.gov/pubmed/20800091
Organophosphates can accumulate, too. This from the US EPA:
From Wikitox:
This says there is little to no accumulation, not no accumulation...
https://academic.oup.com/toxsci/art...cticides-Directly-Activate?redirectedFrom=PDF
https://www.ncbi.nlm.nih.gov/pubmed/20800091
Organophosphates can accumulate, too. This from the US EPA:
From Wikitox:
This says there is little to no accumulation, not no accumulation...
Pyrethroids don't bioaccumulate in humans, from what I have read. I don't think that paper you cited refers to bioaccumulation, but rather to the fact that in the body, during exposure, pyrethroids tend to preferentially concentrate in neurons (but that does not mean they stay in neurons once the exposure is over).
The accumulation in fat tissue only lasts for a few days, according to that statement, so is only a transient issue. Whereas the bioaccumulation of organochlorines is over a period of years, so organochlorine pesticides stick around in the body for a long time. Most most organochlorines have been banned for several decades now, with some exceptions such as dicofol, which is banned in Europe but still used on cotton and fruit crops in the US, and DDT which is still used for malaria control in Africa and parts of Asia.
Of course, Western nations are quite happy to manufacture and export toxic and long banned pesticides to third world countries, where they cause terrible health problems. There is a huge factory somewhere on the East Coast of the US I believe which manufactures large amounts of banned pesticides for exportation to developing countries.
The accumulation in fat tissue only lasts for a few days, according to that statement, so is only a transient issue. Whereas the bioaccumulation of organochlorines is over a period of years, so organochlorine pesticides stick around in the body for a long time. Most most organochlorines have been banned for several decades now, with some exceptions such as dicofol, which is banned in Europe but still used on cotton and fruit crops in the US, and DDT which is still used for malaria control in Africa and parts of Asia.
Of course, Western nations are quite happy to manufacture and export toxic and long banned pesticides to third world countries, where they cause terrible health problems. There is a huge factory somewhere on the East Coast of the US I believe which manufactures large amounts of banned pesticides for exportation to developing countries.
To GettinBetter, my multi-hr hikes and bike rides were moderately severe; I was riding for pleasure and exercise, rather than practicing for extreme sports. The most tiring hikes were in muskeg, which is like walking on piles of pillows while trying to avoid stepping into deep potholes. My rides were on gravel roads with lots of hills; driving on paved roads seemed so effortless in comparison. PEM would show up about 24 hrs later, and if I remember correctly, usually faded sometime that day. I rarely experience multi-day PEM from an activity.
One other thing: my muscle-induced PEM is dependent on how fit those muscles are for the activity. Bike riding might require several hours of pumping those leg muscles to develop PEM (assuming I've been in practice), and even then I'm not sure that it's due to the leg muscles or from other muscles that are being used, such as the arms holding the handlebars. In contrast, a few minutes of washing windows, using arm muscles in ways I don't daily do, will trigger PEM. That's what makes me think that my PEM is triggered by the t-cells activated by damaged muscle cells, and releasing IFN-g, which it does about 24 hrs after the muscle cells are damaged. That's the conclusion I drew from the observations long before I found out about ME/CFS.
One other thing: my muscle-induced PEM is dependent on how fit those muscles are for the activity. Bike riding might require several hours of pumping those leg muscles to develop PEM (assuming I've been in practice), and even then I'm not sure that it's due to the leg muscles or from other muscles that are being used, such as the arms holding the handlebars. In contrast, a few minutes of washing windows, using arm muscles in ways I don't daily do, will trigger PEM. That's what makes me think that my PEM is triggered by the t-cells activated by damaged muscle cells, and releasing IFN-g, which it does about 24 hrs after the muscle cells are damaged. That's the conclusion I drew from the observations long before I found out about ME/CFS.
I was thinking more about the immune/mito feedback issue. Here's a possibility I've come up with:
It starts with something triggering the t-cells. They produce IFN-g, which in turn activates the microglial cells which produce the nastier kynurenines through idole oxidase. Those kynurenines are known to affect mitochondria, and the production of superoxide and peroxynitrite. Indole oxidase uses superoxide to convert tryptophan into kunurenines. A portion of superoxide is converted to peroxynitrite, which destroys IDO (I'm not sure if anything else does control IDO levels). So, anything that affects the ratio of superoxide and peroxynitrite would affect KYN production, and thus the sensitivity of mitochondria to IFN-g. That could be a self-sustaining feedback loop, giving ME/CFS.
Writing this, I realize that it doesn't account for the observation of ME/CFS serum triggering healthy mitochondria into the abnormal state. Maybe a previously undiscovered cytokine? IL-283? Researchers do keep discovering new interleukins, after all.
I don't see anything wrong with posting wild speculations. It might provoke some brilliant researcher into a new line of thought. I'll nobly accept that the nobel prize will go to someone else, who does all the tedious work to verify my magnificent hypothesis.
It starts with something triggering the t-cells. They produce IFN-g, which in turn activates the microglial cells which produce the nastier kynurenines through idole oxidase. Those kynurenines are known to affect mitochondria, and the production of superoxide and peroxynitrite. Indole oxidase uses superoxide to convert tryptophan into kunurenines. A portion of superoxide is converted to peroxynitrite, which destroys IDO (I'm not sure if anything else does control IDO levels). So, anything that affects the ratio of superoxide and peroxynitrite would affect KYN production, and thus the sensitivity of mitochondria to IFN-g. That could be a self-sustaining feedback loop, giving ME/CFS.
Writing this, I realize that it doesn't account for the observation of ME/CFS serum triggering healthy mitochondria into the abnormal state. Maybe a previously undiscovered cytokine? IL-283? Researchers do keep discovering new interleukins, after all.
I don't see anything wrong with posting wild speculations. It might provoke some brilliant researcher into a new line of thought. I'll nobly accept that the nobel prize will go to someone else, who does all the tedious work to verify my magnificent hypothesis.
I'm having a second day of PEM today. I went for a longer drive than usual (~250 km total), and started feeling PEM the next day. Today it feels even worse. I did do a bit of shovelling yesterday, but that shouldn't have been enough to trigger PEM by itself. My arms do feel sore, so I think it's the holding of the steering wheel for a couple of hours that is responsible. I'm not sure whether isostatic exercise (holding arms in position) damages muscles enough to trigger t-cells, or whether it indicates depletion of ATP. Thoughts on that?