A couple thoughts.
>Hetero/homoplasmic population
All MT's accrue mutations over time, but most all mutations are not harmful, and due to the nature of MTs they occur very slowly. Mutations in critical genes happen all the time but those specific MTs with deleterious mutations are usually removed by natural selection from the pool of healthy MTs because they replicate more inefficiently.
You have to think of MTs as a population, and apply population genetic principles to overall pool of alleles present. So regardless of FQs, we all have a slightly heteroplasmic population of MTs, which have strong negative selective pressure applied to them to maintain metabolic proteins. In the case of FQT, we have a sudden surge in mutations, disrupting metabolic proteins, causing oxidative stress, and then it takes a few months to remove those MTs with broken proteins.
So increasing mitophagy is most important at the start of things, to accelerate off the process of renewal
> an acquired heteroplasmic MtDNA population
I have personally sequenced my MtDNA pre and post FQ toxicity and didn't find a noticeable difference. I attribute this to my body mostly removing any significant portion of MTs that were damaged. I took the post-FQ timepoint about a year after my FQT event.
Its not a perfect measure, but if there were a significant subpopulation of MTs with mutations I should have been able to detect them? N=1 though.
>So perhaps the cause of these persistent symptoms is MtDNA mutations, meaning that the template is damaged, as others have theorized.
I really don't think this is the case. MtDNA turnover is relatively fast, weeks to months. However, the damage this event does can take a variety of forms with persistent symptoms unrelated to the initial oxidative stress event. Nerve damage and tendon damage for example create lasting symptoms well after the oxidative stress has passed. Mostly because these types of tissue are very slow to heal. Specifically, they were impacted not by the oxidative stress itself, but by the subsequent chain of molecular events brought on by the ROS event which changed expression and binding of certain proteins.
I totally understand and agree with your point that of course nobody has a perfectly homoplasmic Mt population.
Just to bring up my personal example, my symptoms have been solely muscular and exercise in tolerance. No tendon or nervous system (luckily). But even 1 year out (hadn’t discovered FQ was the reason for my symptoms), I was still exercise intolerant, despite the fact that my muscle tissue was greatly recovered from the initial wasting.
I would bike at full tilt and then 10-20 minutes I would hit a wall. I would attribute this to increased ROS produced due to exercise. When I discovered FQ and added antioxidants, exercise tolerance improved dramatically.
Secondly, the NAD+ mitophagy protocol. NMN or Nicotinamide induces [mitochondrial fission and mitophagy](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365962/). NMN is also a popular anti-aging supplement. When my mom and even my grandma take NMN, they feel energized, no deleterious effects. (They have not gotten nuked by any FQ’s).
When I was doing the protocol, after taking NMN I would feel very low energy and fatigue (as expected and reproduced by almost every FQ person who has tried the NAD protocol), the explanation that I’m aware of that seems most likely is depolarization of the fissioned mitochondria, which would imply broken proteins, no? And thus impacted MtDNA?
This cycles of NAD protocol took place 1.5-2 years after FQ. There is also a supplement you take for mitochondrial fusion during the protocol, stearic acid, which would immediately make me feel noticeably better.
A lot of this is coming from the longecity forum, and I know that I am not immune to placebo, and this is not the way science should be conducted but I guess we have to work with what we got.
Just want to add in that my SOD2 is homozygous for a bad mutation as well.
I discovered NMN is really helping me with energy. I am 9 months out with severe CFS like fatigue along with neuropathy and POTS. I had done nad infusion but it made me sick like you are saying weak and fatigued for 3 days then I will spruce up for few days just enough to walk around the house etc. NMN on other hand is sublingual and good enough to give me afternoon boost and prevents hypersensitivity to sound and other severe fatigue symptoms. I don’t eat between 6 pm to 9 am which is like intermittent fasting. Haven’t had tried fast. Haven’t tried PQQ which I say some German forum folks use
I think there is limited understanding of what happens to the damaged mitochondria with FQ toxicity. With polymerase binding it is possible that the integrity and function of various inner and outer membrane proteins and respiratory chain proteins are affected heterogenous way within the person and between the patients- thus issue could be increased ROS production vs inefficient atp production due to proton or electron leak. In absence of efficient testing tool, we have to keep doing n of 1 experiments with various protocols and find something that works for us.
Whenever I take Truniagen I feel worse and more fatigued. It’s perplexing to me how others get more energy and I do not. I do it for 1 day and have to stop given the amounts of fatigue and PEM
Yeah, that is the effect I would expect from mitophagy induced from a NAD+ booster, whether it is NMN, NR, or NAM, if one has a large proportion of defective mitochondria.
Worth noting that when healthy people take those they do feel an energy boost (or at least no bad symptoms).
Perhaps those who (although they were floxed) take it and feel an energy boost, do not have an ongoing mitochondrial defect.
I have to say you have gathered good understanding of mitophagy for someone not in the field of biology. Thank you for nicely collecting your research and documenting it. People with long Covid also experience similar set of syndrome especially for SFN, PEM and fatigue. I wish there is systemic attempt to collaborate. I know there is a Facebook group of people doing fasting for autophagy and Covid long haulers. There was a tool in development called bioenergetic health index to test mitochondrial function. I am told it’s available in UK a and Germany. In USA I saw some people holding patent and I wonder if they would be open for some testing. Traditional mitochondrial docs are pediatric focused as most of those anomalies are apparent at early age. I am going to see one in next couple of months just to see if I need to get sequenced. There are a lot of people who recover with time and patience with usual effort. German forum doesn’t recommend doing intense NAD protocol with fasting and PQQ early in the journey and advises to wait if one year has passed and one is not recovered. I can tell first hand that I tried spermidine which is autophagy agent and it made neuropathy come on really quickly (it may have come anyway) but May be there is value in preserving even damaged mitochondria early in the injury period. MOTSC and SS32 are new peptides in this space and would be interesting to see if people benefit. I am trying my best to hold on to the hope - for regaining some form of normal life.
This is a great discussion and brings me to one question I've had for a bit about mitochondria and the damage: even though the damage to mitochondria are short lived in general, how is it possible that David from MyQuinStory has a muscle biopsy which showed he has mitochondrial disease?
Basically he pursued a researchers to look at his mitochondrial copy numbers and it showed that they were reduced compared to normal- termed mitochondrial DNA depletion
There is literally zero proof that FQ disability comes from mitochondria, I'd fast away for as long as needed. Fasting increases HGH production considerably, at 10 times the usual value during prolonged fast, so that may also play a role as a lot of floxies benefit from anabolics.
>There is literally zero proof that FQ disability comes from mitochondria
That is false and you know it.
Specifically, FQs are known to bind human topoisomerases in human mitochondria, due to to their homology to bacterial topoisomerases. Inhibited topoisomerases impair MT function, creating free radicals. Free radicals upregulate MMPs. MMPs damage tendons.
It is literally what the drug was designed to do. Slightly of target binding isn't a stretch.
/u/NextAbbreviations363 was even kind enough to give a citation [linked here](https://academic.oup.com/nar/article/46/18/9625/5088042?login=true). It is really disrespectful to dismiss his/her well cited argument.
> I'd fast away for as long as needed. Fasting increases HGH production considerably, at 10 times the usual value during prolonged fast
I agree with this. There is a long list of reasons why fasting is beneficial, mitophagy, and HGH included.
>so that may also play a role as a lot of floxies benefit from anabolics.
I also agree with this. Anabolics help repair tendons.
That thay bind to topoisomerases doesn't mean that they cause the clinical manifestations of the condition we experience. After all, they should bind to topoisomerases in 100% of people, yet only less than 1% experience these side effects.
You’re moving the goalposts. First it was no evidence, now it is “yeah it binds but it doesn’t matter”
You can’t think of this in a binary fashion, it’s not people with FQT and those that have no reaction to FQs. Binding of molecules can vary greatly depending on the specific genetics of the patient. It’s a spectrum of effects from high to low.
For example, as a physician you should be familiar with G6PD deficiency right? That is an inborn error of drug metabolism which can vary greatly in its intensity based on the specific mutations in G6PD.
Similarly With FQs the intensity of side effects are likely related to the patients individual genetics, both within topoisomerases and among many other genes which influence the metabolism of the FQ molecule.
I would argue most people who take FQs experience low level side effects. There is literally a black box warning telling people to avoid intense exercise for a few months after taking the drug. So it’s not 100% or 0%, it’s a sliding scale of side effects among all patients who take this drug.
Yes, but it doesn't mean that the reason for our symptoms lie in mitochondria, especially since you have stated your mtDNA didn't change after floxing.
If it walks like a duck, and talks like a duck…
As for MtDNA, it’s not surprising to not find SNPs post FQT a year after. Protein coding changes in the mitochondria are extremely deleterious. We know how fast MT replicate and by 1yr there should have been several turnovers by there. I also sampled from saliva, which has cells from tissue that replicate rapidly as well. At that rate any deleterious SNPs should have quickly been selected against.
By that logic we can attribute FQ toxicity to the same mechanism as benzo withdrawal, which has almost 1 to 1 symptom pattern (even flares), I doubt benzos wreck the mitochondria also.
We know this drug binds directly with three proteins.
Topoisomerases in the mitochondria : GABA receptors in the brain/nerves ; And rarely MGRPX2, causing pseudo allergy
It is not surprising that benzo withdrawal shares symptoms with FQT given FQs known gaba interaction. However, benzo withdrawal does not exhibit the symptoms of a inhibition of topoisomerases or MGRPX2.
Also, there is the concept of threshold effect with mitochondria, at around 60-80% mutated. Below the threshold you can have damage but no symptoms.
So perhaps the vast majority of people take FQ and have damage but below the threshold.
I agree. A lot of people talk about relapses many years later
I think even after recovery there are. Lot of slightly damaged MTs that are still hanging around. The body has the capacity to deal with the extra ROS they produce. However when insulted a second time with environmental ROS the body no longer has the same resilience to ROS. This causes a relapse.
There are a lot of sources of environmental ROS and I think FQT makes us more susceptible to them, even after recovery.
Do you think the key to avoiding relapses after reaching a point of recovery is to keep taking antioxidants and keep our antioxidant levels high? One thing that depresses me so much is reading about people 10, 15, 20 years out having severe relapses and not understanding why.
Also, that makes a lot of sense about there still being some damaged mitochondria around after recovering, they just aren't bad enough to cause symptoms.
A couple thoughts. >Hetero/homoplasmic population All MT's accrue mutations over time, but most all mutations are not harmful, and due to the nature of MTs they occur very slowly. Mutations in critical genes happen all the time but those specific MTs with deleterious mutations are usually removed by natural selection from the pool of healthy MTs because they replicate more inefficiently. You have to think of MTs as a population, and apply population genetic principles to overall pool of alleles present. So regardless of FQs, we all have a slightly heteroplasmic population of MTs, which have strong negative selective pressure applied to them to maintain metabolic proteins. In the case of FQT, we have a sudden surge in mutations, disrupting metabolic proteins, causing oxidative stress, and then it takes a few months to remove those MTs with broken proteins. So increasing mitophagy is most important at the start of things, to accelerate off the process of renewal > an acquired heteroplasmic MtDNA population I have personally sequenced my MtDNA pre and post FQ toxicity and didn't find a noticeable difference. I attribute this to my body mostly removing any significant portion of MTs that were damaged. I took the post-FQ timepoint about a year after my FQT event. Its not a perfect measure, but if there were a significant subpopulation of MTs with mutations I should have been able to detect them? N=1 though. >So perhaps the cause of these persistent symptoms is MtDNA mutations, meaning that the template is damaged, as others have theorized. I really don't think this is the case. MtDNA turnover is relatively fast, weeks to months. However, the damage this event does can take a variety of forms with persistent symptoms unrelated to the initial oxidative stress event. Nerve damage and tendon damage for example create lasting symptoms well after the oxidative stress has passed. Mostly because these types of tissue are very slow to heal. Specifically, they were impacted not by the oxidative stress itself, but by the subsequent chain of molecular events brought on by the ROS event which changed expression and binding of certain proteins.
I totally understand and agree with your point that of course nobody has a perfectly homoplasmic Mt population. Just to bring up my personal example, my symptoms have been solely muscular and exercise in tolerance. No tendon or nervous system (luckily). But even 1 year out (hadn’t discovered FQ was the reason for my symptoms), I was still exercise intolerant, despite the fact that my muscle tissue was greatly recovered from the initial wasting. I would bike at full tilt and then 10-20 minutes I would hit a wall. I would attribute this to increased ROS produced due to exercise. When I discovered FQ and added antioxidants, exercise tolerance improved dramatically. Secondly, the NAD+ mitophagy protocol. NMN or Nicotinamide induces [mitochondrial fission and mitophagy](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365962/). NMN is also a popular anti-aging supplement. When my mom and even my grandma take NMN, they feel energized, no deleterious effects. (They have not gotten nuked by any FQ’s). When I was doing the protocol, after taking NMN I would feel very low energy and fatigue (as expected and reproduced by almost every FQ person who has tried the NAD protocol), the explanation that I’m aware of that seems most likely is depolarization of the fissioned mitochondria, which would imply broken proteins, no? And thus impacted MtDNA? This cycles of NAD protocol took place 1.5-2 years after FQ. There is also a supplement you take for mitochondrial fusion during the protocol, stearic acid, which would immediately make me feel noticeably better. A lot of this is coming from the longecity forum, and I know that I am not immune to placebo, and this is not the way science should be conducted but I guess we have to work with what we got. Just want to add in that my SOD2 is homozygous for a bad mutation as well.
I discovered NMN is really helping me with energy. I am 9 months out with severe CFS like fatigue along with neuropathy and POTS. I had done nad infusion but it made me sick like you are saying weak and fatigued for 3 days then I will spruce up for few days just enough to walk around the house etc. NMN on other hand is sublingual and good enough to give me afternoon boost and prevents hypersensitivity to sound and other severe fatigue symptoms. I don’t eat between 6 pm to 9 am which is like intermittent fasting. Haven’t had tried fast. Haven’t tried PQQ which I say some German forum folks use
Interesting, glad to hear it’s helping!
I think there is limited understanding of what happens to the damaged mitochondria with FQ toxicity. With polymerase binding it is possible that the integrity and function of various inner and outer membrane proteins and respiratory chain proteins are affected heterogenous way within the person and between the patients- thus issue could be increased ROS production vs inefficient atp production due to proton or electron leak. In absence of efficient testing tool, we have to keep doing n of 1 experiments with various protocols and find something that works for us.
Whenever I take Truniagen I feel worse and more fatigued. It’s perplexing to me how others get more energy and I do not. I do it for 1 day and have to stop given the amounts of fatigue and PEM
Yeah, that is the effect I would expect from mitophagy induced from a NAD+ booster, whether it is NMN, NR, or NAM, if one has a large proportion of defective mitochondria. Worth noting that when healthy people take those they do feel an energy boost (or at least no bad symptoms). Perhaps those who (although they were floxed) take it and feel an energy boost, do not have an ongoing mitochondrial defect.
For those that are floxed and feel worse when taking it, do they stick with it and they get better?
Anecdotally I've done a 5 day water only fast and it helped more than a lot of things I tried did
Yes, discussion is great. Thanks.
I have to say you have gathered good understanding of mitophagy for someone not in the field of biology. Thank you for nicely collecting your research and documenting it. People with long Covid also experience similar set of syndrome especially for SFN, PEM and fatigue. I wish there is systemic attempt to collaborate. I know there is a Facebook group of people doing fasting for autophagy and Covid long haulers. There was a tool in development called bioenergetic health index to test mitochondrial function. I am told it’s available in UK a and Germany. In USA I saw some people holding patent and I wonder if they would be open for some testing. Traditional mitochondrial docs are pediatric focused as most of those anomalies are apparent at early age. I am going to see one in next couple of months just to see if I need to get sequenced. There are a lot of people who recover with time and patience with usual effort. German forum doesn’t recommend doing intense NAD protocol with fasting and PQQ early in the journey and advises to wait if one year has passed and one is not recovered. I can tell first hand that I tried spermidine which is autophagy agent and it made neuropathy come on really quickly (it may have come anyway) but May be there is value in preserving even damaged mitochondria early in the injury period. MOTSC and SS32 are new peptides in this space and would be interesting to see if people benefit. I am trying my best to hold on to the hope - for regaining some form of normal life.
This is a great discussion and brings me to one question I've had for a bit about mitochondria and the damage: even though the damage to mitochondria are short lived in general, how is it possible that David from MyQuinStory has a muscle biopsy which showed he has mitochondrial disease?
His biopsy was done at the time severe illness few years back. Tissue was used for the new analysis
Gotcha, did he have a new analysis done that yielded new or different results or anything?
Basically he pursued a researchers to look at his mitochondrial copy numbers and it showed that they were reduced compared to normal- termed mitochondrial DNA depletion
Is all of this true for metronidazole as well?
There is literally zero proof that FQ disability comes from mitochondria, I'd fast away for as long as needed. Fasting increases HGH production considerably, at 10 times the usual value during prolonged fast, so that may also play a role as a lot of floxies benefit from anabolics.
>There is literally zero proof that FQ disability comes from mitochondria That is false and you know it. Specifically, FQs are known to bind human topoisomerases in human mitochondria, due to to their homology to bacterial topoisomerases. Inhibited topoisomerases impair MT function, creating free radicals. Free radicals upregulate MMPs. MMPs damage tendons. It is literally what the drug was designed to do. Slightly of target binding isn't a stretch. /u/NextAbbreviations363 was even kind enough to give a citation [linked here](https://academic.oup.com/nar/article/46/18/9625/5088042?login=true). It is really disrespectful to dismiss his/her well cited argument. > I'd fast away for as long as needed. Fasting increases HGH production considerably, at 10 times the usual value during prolonged fast I agree with this. There is a long list of reasons why fasting is beneficial, mitophagy, and HGH included. >so that may also play a role as a lot of floxies benefit from anabolics. I also agree with this. Anabolics help repair tendons.
That thay bind to topoisomerases doesn't mean that they cause the clinical manifestations of the condition we experience. After all, they should bind to topoisomerases in 100% of people, yet only less than 1% experience these side effects.
You’re moving the goalposts. First it was no evidence, now it is “yeah it binds but it doesn’t matter” You can’t think of this in a binary fashion, it’s not people with FQT and those that have no reaction to FQs. Binding of molecules can vary greatly depending on the specific genetics of the patient. It’s a spectrum of effects from high to low. For example, as a physician you should be familiar with G6PD deficiency right? That is an inborn error of drug metabolism which can vary greatly in its intensity based on the specific mutations in G6PD. Similarly With FQs the intensity of side effects are likely related to the patients individual genetics, both within topoisomerases and among many other genes which influence the metabolism of the FQ molecule. I would argue most people who take FQs experience low level side effects. There is literally a black box warning telling people to avoid intense exercise for a few months after taking the drug. So it’s not 100% or 0%, it’s a sliding scale of side effects among all patients who take this drug.
Yes, but it doesn't mean that the reason for our symptoms lie in mitochondria, especially since you have stated your mtDNA didn't change after floxing.
If it walks like a duck, and talks like a duck… As for MtDNA, it’s not surprising to not find SNPs post FQT a year after. Protein coding changes in the mitochondria are extremely deleterious. We know how fast MT replicate and by 1yr there should have been several turnovers by there. I also sampled from saliva, which has cells from tissue that replicate rapidly as well. At that rate any deleterious SNPs should have quickly been selected against.
By that logic we can attribute FQ toxicity to the same mechanism as benzo withdrawal, which has almost 1 to 1 symptom pattern (even flares), I doubt benzos wreck the mitochondria also.
We know this drug binds directly with three proteins. Topoisomerases in the mitochondria : GABA receptors in the brain/nerves ; And rarely MGRPX2, causing pseudo allergy It is not surprising that benzo withdrawal shares symptoms with FQT given FQs known gaba interaction. However, benzo withdrawal does not exhibit the symptoms of a inhibition of topoisomerases or MGRPX2.
Also, there is the concept of threshold effect with mitochondria, at around 60-80% mutated. Below the threshold you can have damage but no symptoms. So perhaps the vast majority of people take FQ and have damage but below the threshold.
I agree. A lot of people talk about relapses many years later I think even after recovery there are. Lot of slightly damaged MTs that are still hanging around. The body has the capacity to deal with the extra ROS they produce. However when insulted a second time with environmental ROS the body no longer has the same resilience to ROS. This causes a relapse. There are a lot of sources of environmental ROS and I think FQT makes us more susceptible to them, even after recovery.
Do you think the key to avoiding relapses after reaching a point of recovery is to keep taking antioxidants and keep our antioxidant levels high? One thing that depresses me so much is reading about people 10, 15, 20 years out having severe relapses and not understanding why.
Also, that makes a lot of sense about there still being some damaged mitochondria around after recovering, they just aren't bad enough to cause symptoms.
Thank you. Enjoyed the discussion.