Greetings. This is my first post here, and my reason for joining. I'd just like to draw some attention to the mPTP (mitochondrial permeability transition pore), as I feel it rarely comes up in any of the research I've read in any greater capacity than an aside - I've not seen it posed as a core mechanism.
As a disclaimer, I myself am not credentialed - the following hypothesis is more of "a sick guy's best attempt at connecting the dots". That being said, I certainly find this idea interesting and, perhaps plausible enough to pose as a probable mechanism, and feel it would be amiss to not at least bring this to the attention of a group capable of either shooting it down logically, or exploring the notion further, if indeed it leads somewhere.
To clarify, the mPTP is a channel that can be induced in the inner-membrane of the mitochondria. It can be induced transiently, or for an extended period - the latter of these is where the most damage occurs. When the mPTP is induced, two key things happen as a direct consequence:
In regulatory T-cell mitochondria, this can cause the cell to become dysfunctional, which, in addition to the release of mtDNA, further compounds the potential for autoimmunity. Among other things, the mPTP can be induced by:
Each of the above stressors induces the mPTP to a different degree - most of these alone, at regular day-to-day levels, are insufficient to induce the mPTP to a problematic degree in a healthy individual. My idea is that when multiple of them co-occur - especially alongside a virus which specifically targets mPTP induction - you get an escalation of this incremental energy baseline deterioration that we see in ME/CFS. And each time it happens, there's less remaining mitochondrial capacity to buffer the damage, so it takes less 'stress' to surpass your ATP availability.
If one's energy baseline corresponds to their remaining mitochondrial production capacity, then a reduction of said baseline by further calcium overloading makes sense; at a certain point, you may have too little available energy to continue mitogenesis, causing you to get stuck at these distinct baselines - we cannot replenish mitochondria as fast as we are rendering them non-functional / depleting them. The less your remaining mitochondrial function, the more severe your condition.
Of course, recoveries do happen - but they aren't too common. And those in remission seem to have a tendency to fall ill again, which seems to suggest in many cases, a permanent state of variable global mitochondrial sufficiency. This is basically my hypothesis, distilled. I've kept it concise, on account of brain fog, but I hope that even this rough picture demonstrates the idea well enough. If any of this reads as "you have no idea what you're talking about", then, apologies.
The following are footnotes, but still worth mentioning:
Magnesium and NADH, both quite common in ME/CFS supplement stacks, help to prevent mPTP induction.
(https://pmc.ncbi.nlm.nih.gov/articles/PMC5393273/)
Additionally, while I'm not able to find the actual source, an article from the ME Association states that cyclosporine has shown "good results".
(https://meassociation.org.uk/2021/0...ging-treatment-options-for-autoimmune-me-cfs/)
This seems notable, not because cyclosporine is an immunosuppressant, but specifically because cyclosporine A inhibits mPTP opening by binding cyclophilin D, a regulator of the pore’s gating.
(https://www.nature.com/articles/cddis201480)
As a disclaimer, I myself am not credentialed - the following hypothesis is more of "a sick guy's best attempt at connecting the dots". That being said, I certainly find this idea interesting and, perhaps plausible enough to pose as a probable mechanism, and feel it would be amiss to not at least bring this to the attention of a group capable of either shooting it down logically, or exploring the notion further, if indeed it leads somewhere.
To clarify, the mPTP is a channel that can be induced in the inner-membrane of the mitochondria. It can be induced transiently, or for an extended period - the latter of these is where the most damage occurs. When the mPTP is induced, two key things happen as a direct consequence:
* Ions begin to move in to the mitochondria through the open channel. When this happens consistently, or for an extended period, the mitochondria loses the electrochemical gradient required to build ATP, and, at worst (can) die completely.
* mtDNA can be released as a downstream consequence, provoking an immune response.
In regulatory T-cell mitochondria, this can cause the cell to become dysfunctional, which, in addition to the release of mtDNA, further compounds the potential for autoimmunity. Among other things, the mPTP can be induced by:
* Numerous different viruses (including SARS-CoV-2) in the event of an infection.
* Certain chemicals (including some antidepressants, like Sertraline).
* Chronic physical and mental stress (β-adrenergic stimulation, at least demonstrated in-vivo)
* The downstream effects of high glucose.
Each of the above stressors induces the mPTP to a different degree - most of these alone, at regular day-to-day levels, are insufficient to induce the mPTP to a problematic degree in a healthy individual. My idea is that when multiple of them co-occur - especially alongside a virus which specifically targets mPTP induction - you get an escalation of this incremental energy baseline deterioration that we see in ME/CFS. And each time it happens, there's less remaining mitochondrial capacity to buffer the damage, so it takes less 'stress' to surpass your ATP availability.
If one's energy baseline corresponds to their remaining mitochondrial production capacity, then a reduction of said baseline by further calcium overloading makes sense; at a certain point, you may have too little available energy to continue mitogenesis, causing you to get stuck at these distinct baselines - we cannot replenish mitochondria as fast as we are rendering them non-functional / depleting them. The less your remaining mitochondrial function, the more severe your condition.
Of course, recoveries do happen - but they aren't too common. And those in remission seem to have a tendency to fall ill again, which seems to suggest in many cases, a permanent state of variable global mitochondrial sufficiency. This is basically my hypothesis, distilled. I've kept it concise, on account of brain fog, but I hope that even this rough picture demonstrates the idea well enough. If any of this reads as "you have no idea what you're talking about", then, apologies.
The following are footnotes, but still worth mentioning:
Magnesium and NADH, both quite common in ME/CFS supplement stacks, help to prevent mPTP induction.
(https://pmc.ncbi.nlm.nih.gov/articles/PMC5393273/)
Additionally, while I'm not able to find the actual source, an article from the ME Association states that cyclosporine has shown "good results".
(https://meassociation.org.uk/2021/0...ging-treatment-options-for-autoimmune-me-cfs/)
This seems notable, not because cyclosporine is an immunosuppressant, but specifically because cyclosporine A inhibits mPTP opening by binding cyclophilin D, a regulator of the pore’s gating.
(https://www.nature.com/articles/cddis201480)
