Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, Paper Pub. 4/1/20 - Dr. Prusty

[Marylib]

@Mary - I may have this in the wrong place, but I am trying to share research on the "hypermetabolic" state rather the the hypometabolic conclusion of Prusty and Naviaux. Paul Fisher came out with one last year and one this year. Here is the most recent one, for the smart guys to try and reconcile, if such a thing is possible. Sadly, the clinician who supplied the test subjects passed away last year.

https://www.mdpi.com/1422-0067/21/3/1074

 

[ZeroGravitas]

I am trying to share research on the "hypermetabolic" state rather the the hypometabolic conclusion of Prusty and Naviaux.

So, it's funny you ask, because it's one of the few things I've commented on several times in the past...

I've not looked at that 2020 Missailidis paper [mdpi], yet. But I read into the 2019 paper that you linked in your [previous comment], by McGregor and Armstrong, etc - PEM associated with hypermetabolism [mdpi], at the time... [PhoenixRising] thread, too.

I've now totally forgotten the lay of the metabolites, pathways and enzymes for the 5th time; all just a soup of arbitrary names running through my sieve-brain again, so I'm mostly generalising from vague notions, here (so as always correct me!)... But I commented on Cort's article explaining the research (I'm pretty much the only person with an avatar pic on there, heh):

I think your talk of “hypermetabolic” states may be a little confusing for some. Given Naviaux described ME/CFS as hypometabolic and dauer like.

I don’t *think* there’s any contradiction here, is there? It’s *just* the anaerobic metabolism that is hyper-active. Reduced glucose metabolism causing (presumably?) the observed amino acid depletion. And all the other types of lowered metabolites too…?

So hypo/hyper are two sides of the same shift in energy metabolism:
• Reduced (hypo) use of oxygen in mitochondria for oxidative phosphorylation (electron transport chain, etc with lactic acid as an end-point).
• Increased (hyper) anaerobic glycolysis, which is far less efficient, way more resource intensive and so catabolic (muscle breakdown).

In Naviaux's terms, I believe the cells in Prusty's lab experiment were in the CDR1 state, because he talks about "M1-proinflammatory form of mitochondria". Fig.2 from "Cell danger response Biology—The new science[...]" [ScienceDirect]:

CDR states linked to their energy metaboloism type in Fig.1 of same paper (don't worry about other details):


Note, that I'm not sure what form of mitochondria are normal for the cancer cell lines... As they are probably in a perpetual state of rapid growth, I'd guess M0 - aerobic glycolysis...?

It's one of the questions I wanted to ask Prusty, as they never mention the different CDR numbers in the latest paper, despite being a colaboration with Naviaux. (Incidentally, Cort said he conferred with Naviaux, not Prusty, in doing his write-up.)

If the M0 type mitochondria seen in the HHV-6 experiments are representative of ME/CFS, then I'm wondering if Naviaux had CFS mis-categorised as a CDR3 disease (see row D of above diagram). Or if the categories themselves need adjustment...?


Going back to energy production. A 2016 paper by Lawson et al. saw "Elevated Energy Production in Chronic Fatigue SyndromePatients" [jnsci]. [PhoenixRising] thread. Again, there was no contradiction with hypometabolism, they had just washed the patient's (immune) blood cells and given them a medium in which they then thrived (something Prusty mentions in passing in his video talk, embedded above). Principle author, Xinnan Wang, replied to my emailed question:

(3) Was the team aware of the potential for altering the PBMN cell's characteristics by having them in a growth medium (for 2-3 days, was it?), free of any factors that might be found in subject's serum? (The word from a number of metabolomics researchers is that they are sure there is something in patient's blood that is inhibiting mitochondria and are now trying to isolate this factor(s).)

Yes of course these cells are very different from in vivo. However, as explained in the background this was the only option at the time and even if cultured in vitro these cells are still useful for studying mitochondrial function and ultrastructure.

So, greatly increased glycolysis, which Cort's write up talked more about. With slightly less than normal ATP from mitochondria, but double the normal from outside the mitos (glycolytically):

Prusty's new study saw only a modestly lower overall ATP production (below). Different tissue types of the cells, of course. I think they decided (unless I'm misinterpreting) the overall ~2x rise (above), entirely from glycolysis, might be due to patient's immune cell's ongoing activation. Changes previously hidden, in vivo, suppressed by the serum factor...?

[Fig.5C - A549 cells cultured in respective serum]

Again, I don't know how much this modest difference in cellular ATP levels would be reflected in (non-cancerous) patient cells... M2 mitos produce a lot more ATP than M0 would (which are geared towards structural metabolites, etc, instead).

I'm also not sure how much one would expect to see the ATP levels drop, in practice...? Such an important metabolite, would a cell that can't make enough quickly start slowing or shutting down uses of it, triage rather than run out...? At any rate, the levels are a snapshot and don't necessarily say much about the flux (rate of production) of ATP...?

 

[gregh286]

I have this too, and often spoken about it. I can wake at 3 am and feel not too bad, then go back to sleep and wake at 6 or 7 feeling like death. So strange. It is like something is being released when in sleep, at different times...

Absolutely.
It's so obvious that if I do wake at 3 or 4 i never go back to sleep even though the eyes are hanging out of me.
More physical/ lack.of.sleep tiredness reduces that ghastly laden legged fatigue.
Try explaining that one to gp. I'm less fatigued when I'm more tired.

 

[ZeroGravitas]

I'm less fatigued when I'm more tired.

Otherwise healthy ADHDers have this kind of paradoxical benefit from lack of sleep, too. It's extremely common for them to work best after everyone else has gone to bed. Some even claim they concentrate best after a night (or two!) with no sleep at all.

I'm thinking it's probably mostly from increased stress hormones: cortisol is anti-inflammatory, liberates glucose and promotes aerobic energy production. (And also gets neurotransmitters flowing for motivated movement - dopamine, norepinephrine, whatever.) Which might counteract a couple of our issues, temporarily.

I know I feel terrible if woken a couple hours early, the worst time for me to try to get up. I think this is because my sleep structure is so out of whack, backwards - from an EEG tracking headband alarmclock (I used for 6 months) I saw I get most of my deep sleep at the end of the 'night'. I also have a 26h long, rotating, cycle (25 at time of monitoring).

The immune system is most active during deep sleep, right? So feeling worst first thing makes sense. Although, after I've taken a couple hours to get up, for me the early part of the day is my most productive. Again, maybe cortisol from hunger getting me moving. Maybe the lack of food needing digesting and causing inflamation via (leaky gut), too. Shrug.

I was also wondering if cells might fail to return to their full healthy state after a sleep period... Like is there a check gate for that, too? (Could they enter into CDR3 or something?)

Sometimes if I wake up to pee or whatever at say 4-5am then go back to sleep I wake up more refreshed than if I just slept right through.

Yeah, kinda felt that a little, maybe. I also tend to wake up about 1/3 way through sleep, overheated (in the last year or two). Struggling to control body temp in bed. Maybe thyroid. But sleep disturbance can come from hypogycemia, right? Was someone metioning that above? And ME/CFS certainly seems to have trouble with glucose metabolism.

 

[ZeroGravitas]

I have some ideas of why this is happening, but I've beaten back 7 viral and bacterial infections, including EBV abd HHV6, that I didn't feel sick from, only fatigue, and gave find a lot of work on my mitos, and this oxidative stress did not go away.

Sorry, been meaning to reply to you on these. But been fatiguing/crashing, plus feel wholly inadequate to talk about the ins and outs of mitocondria and experimental findings pertaining. Humbled by the great many things you've each tried, battled against and overcome. I'm lucky not to ever had to have fought so many crazy symptoms, or any obvious infections...

I've felt its unviably difficult to try to manually correct all my metabolic deficits, via testing and targetted supplementing, or just trying so many protocols, which I'm bad or unhappy at following. Kinda waiting for a revelatory linchpin to be found, so I can fix that (fingers crossed) and then have things be more or less plain sailing, hopefully. I.e. I'd expect a fair length road to full recovery, but more like re-feeding from starvation, rebuilding metabolite pools, with a body that's not pulling backwards, wanting to slide downhill.

If there is a high level cause, that's directing all our cells to make ROS, for example, then turning that tap off's going to far easier than constantly mopping up ever more of it (and all the rest of the issues).

Do, the recycling and repair mechanisms offer a chance to improve ones crop of mitos in a reasonable but not immediate timeframe.

Like I say, I'm no mito expert, haven't read much on them and can't keep much of any of the details in my head for more than a week (if I'm lucky)...

But the way I understand it is, your mitos can recover to the level of your least damaged mtDNA, in each cell. By sharing those good genes during fusion, like offspring inherit dominant genes, I think. And continuously destroying fissioned mitos in the lysosome.

Should be a matter of months to maximise their health (to the level of the least damaged, which will be less good with age). That's after removal anything that's causing them new damage. Maybe that's a far longer process with heavy metal/toxin accumulation...?

I believe mito recycling can be sped up in various ways, too, like fasting, which will trigger cells to start breaking down some of their machinery to burn it for fuel. Probably (whole body) thermal treatments do something...? Lotta clever health researcher-advocates always raving about heat-shock proteins, saunas and such.

 

[stefanosstef]

I experienced the same re: sleep. I'll add that I have also had good results from methotrexate and to a lesser degree other DMARDS.

All in all to me there seems to be an autoimmune condition here that results in something being released in the later stages of sleep.

If that is the something in the blood, it may be that which creates mito fission.

I experience the exact same thing with my sleep.

Edit:This is a chemotherapy drug.Not judging at all but to me it seems insane to try something like this.How was your experience?

 

[Learner1]

I've felt its unviably difficult to try to manually correct all my metabolic deficits, via testing and targetted supplementing, or just trying so many protocols, which I'm bad or unhappy at following. Kinda waiting for a revelatory linchpin to be found, so I can fix that (fingers crossed) and then have things be more or less plain sailing, hopefully. I.e. I'd expect a fair length road to full recovery, but more like re-feeding from starvation, rebuilding metabolite pools, with a body that's not pulling backwards, wanting to slide downhill.

Here's the rub. There's only one drug for mito disease, and there are more problems with mitos than solutions.

For what you wish to happen, best case, it's probably 5-10 years from lab bench to patient treatment. If you have that amount of time to sit around patiently waiting, wonderful. I don't. I've been sick for 5.5 years and have wasted enough of my life. I've found that by reading the research, connecting the dots, doing some strategic labwork to test out theories, and running some n=1 experiments based on sound logic is a faster way to improving my function now. I'm under no illusion that it's a cure, but I suspect my mitos and telomeres have been so beat up over time, that's not a realistic goal. Perfection is not what I want, a high quality day to day life is.

If there is a high level cause, that's directing all our cells to make ROS, for example, then turning that tap off's going to far easier than constantly mopping up ever more of it (and all the rest of the issues)

The investigations I've done have shown me that there are multiple sources of ROS, including the mitochondria themselves. The list can be summarized by Naviaux's list of cell dangers, along with a couple things not on his list.

I've found my body is creating an extraordinary amount of oxidative stress. Even after removing certain cell dangers, it seems there's a deranged creation of oxidative stress, it maybe it's just I'm lousy at dealing with it, with adequate SOD, catalase, glutathione, etc. But, I've found that fighting this battle and reducing it as much as I can had been a key to increasing function and quality of life. And getting rid of PEM. Investigating this and related nitrosative stress is where I'm most focused these days, and these ARE known issues in ME/CFS.

Like I say, I'm no mito expert, haven't read much on them and can't keep much of any of the details in my head for more than a week (if I'm lucky)...

I can guarantee your doctors aren't, either. There are very few experts, and those that are focus on genetic mito diseases, not acquired mito dysfunction.

Well worth learning as much as you can. Mitos are the key to energy production. If they don't work right, we are screwed.

But the way I understand it is, your mitos can recover to the level of your least damaged mtDNA, in each cell. By sharing those good genes during fusion, as offspring inherit dominant genes, I think. And continuously destroying fissioned mitos in the lysosome.

That's on the right track...

Should be a matter of months to maximise their health (to the level of the least damaged, which will be less good with age). That's after removal anything that's causing them new damage. Maybe that's a far longer process with heavy metal/toxin accumulation...?
.

That's the idea, and pretty much what I've had success with doing. Yes, toxins can get into the mitochondria and if they're there, removing them is a key to having functional mitochondria. Another issue that's more common than ME/CFS patients are aware of is oxalates, sharp crystals that damage mitos and promote oxidative stress, due to microbiome dysruption after antibiotic use.

I believe mito recycling can be sped up in various ways, too, like fasting, which will trigger cells to start breaking down some of their machinery to burn it for fuel. Probably (whole body) thermal treatments do something...? Lotta clever health researcher-advocates always raving about heat-shock proteins, saunas and such.

Layering different strategies as in the Seyfried/D'Agostino/Nicolson article on the Correction of Mitochondria is definitely a the way to get there faster.

I greatly doubt one magic pill is going to fix what's gone wrong. The horse is too far out of the barn and too many things have gone wrong.

 

[Wishful]

It's going to take more going to fix cells that have HHV6 embedded in the DNA and mitochondria that are fragmented. There's a lot of collateral damage to cells and mitochondria. Yes, it's harder, but that's what we're faced with.

If ME was due to damaged cells, then the body shouldn't be able to switch back to the healthy state over a period of minutes, and then switch back to full ME just as fast a few hours later. So no, I don't think ME involves serious long-term cellular damage. I think it's a feedback loop biased towards positive feedback. Hidden viral infections might be part of that bias, or it might be something that the biased system reacts to.


BTW, maybe because this thread was started by moving it from another thread, I never noticed it start up. Did it show up on the 'new threads' list?

 

[Learner1]

If ME was due to damaged cells, then the body shouldn't be able to switch back to the healthy state over a period of minutes, and then switch back to full ME just as fast a few hours later. So no, I don't think ME involves serious long-term cellular damage. I think it's a feedback loop biased towards positive feedback.

I don't think my body does that. I gradually got worse and have gradually gotten better. No on and off states at all. And I've had done serious long term damage, likely due to my history of chemo drugs and fluoroquinolones. I can't speak for everyone else, though I suspect others may have similar characteristics yet others don't.

 

[Marylib]

@Wishful My internet is lousy, so I can't open my messages, but I am assuming the admin I tagged with my comment moved my post to another thread, for clarity.

If ME was due to damaged cells, then the body shouldn't be able to switch back to the healthy state over a period of minutes, and then switch back to full ME just as fast a few hours later. So no, I don't think ME involves serious long-term cellular damage. I think it's a feedback loop biased towards positive feedback. Hidden viral infections might be part of that bias, or it might be something that the biased system reacts to.


BTW, maybe because this thread was started by moving it from another thread, I never noticed it start up. Did it show up on the 'new threads' list?

 

[stefanosstef]

I don't think my body does that. I gradually got worse and have gradually gotten better. No on and off states at all. And I've had done serious long term damage, likely due to my history of chemo drugs and fluoroquinolones. I can't speak for everyone else, though I suspect others may have similar characteristics yet others don't.

What supplements exactly do you suggest for recusing ROS?
I have dealt with fluoroquinolone toxicity syndrome, not myself but I helpe my gf, going out in the sun, exercising and taking mitoQ+PQQ should slowly refresh your mitochondria, but probably you've already tried it.

 

[Marylib]

@ZeroGravitas I have read that something similar happens with depression, in terms of sleep deprivation making the symptoms more bearable. There is so much to learn about the immune system and various "psychiatric disorders" - neuro/immune inflammation, etc.
When I have been extra-sick, getting a couple hours sleep at a time has made things more bearable in terms of the usual sleep reversal - sleeping all day and never waking up until things are quiet. So many people have to live that way and it is very isolating. You never see the sun. A friend of mine whose mother had schizophrenia said her mom had to live that way, just to get some relief from the relative peace and quiet. My brother with ADHD seems to do okay with shift work, just taking short naps.

Otherwise healthy ADHDers have this kind of paradoxical benefit from lack of sleep, too. It's extremely common for them to work best after everyone else has gone to bed. Some even claim they concentrate best after a night (or two!) with no sleep at all.

I

 

[Wishful]

A couple of replies here have mentioned how mitochondria are constantly repairing & recycling themselves, and have a lifespan of 2-4 weeks. Has anyone here come across mention of precise and consistent timing for mitochondria (or other cellular components) that would fit 21 days, +/- hours rather than days? I've been wondering why a single dose of T2 would 'reset' something, preventing a worsening of my symptoms for a consistent 21 days. T2 is involved in RNA transcription, so I could imagine it allowing production of something that isn't being produced enough at lower levels of T2. I wonder if mitochondria have an internal timer, so that 21 days (or whatever) after they're created, they trigger a self-destruct sequence. Is there a biology forum where such questions might get answered?

 

[Learner1]

What supplements exactly do you suggest for recusing ROS?

The ones my lab testing suggests I need:

• A
• C
• E
• ALA
• Glutathione precursors (B's, NAC)
• Liposomal glutathione
• Quercetin
• Curcumin
• Resveratrol
• Mercolas Purple Defense
• CoQ10

I have dealt with fluoroquinolone toxicity syndrome, not myself but I helpe my gf, going out in the sun, exercising and taking mitoQ+PQQ should slowly refresh your mitochondria, but probably you've already tried it.

Sure have taken them. I take MitoQ and ubiquinol. PQQ did nothing for me. I live in Seattle, notorious for lack of sun, but keep my D high.

Not sure where you got the idea that sun, PQQ and MitoQ will "slowly refresh your mitochondria."

To refresh ones mitochondria, one needs to remove the things that are damaging them, and remove the toxins in them, like the black stuff here which is arsenic:

Then, one needs to support MnSOD and catalase, as well as glutathione, and reduce superoxide and peroxynitrite production.

And, if membranes have been damaged, reducing efficiency of pushing H+ through them, one needs to repair them with phospholipids, like. NT Factor or equivalent.

 

[Learner1]

A couple of replies here have mentioned how mitochondria are constantly repairing & recycling themselves, and have a lifespan of 2-4 weeks. Has anyone here come across mention of precise and consistent timing for mitochondria (or other cellular components) that would fit 21 days, +/- hours rather than days? I've been wondering why a single dose of T2 would 'reset' something, preventing a worsening of my symptoms for a consistent 21 days. T2 is involved in RNA transcription, so I could imagine it allowing production of something that isn't being produced enough at lower levels of T2. I wonder if mitochondria have an internal timer, so that 21 days (or whatever) after they're created, they trigger a self-destruct sequence. Is there a biology forum where such questions might get answered?

I don't recall any specific timing being mentioned. Done of it may be ygst they vary by tissue. However, one needs adequate asparagine to have apoptosis of mitos. My mito content went from under 50% of normal to 150% of normal when I became deficient in asparagine, then returned to the original value when asparagine was replete.

Attached is the paper that tipped me off to this dynamic.

If you have a specific times cycle, you may want to look into hormones or other things that might reach a threshold and dissipate.

 

[ZeroGravitas]

I've edited/updated my paper summary post a bunch [above]. I hadn't realised that the green florescent mitochondria images were taken in a second batch of U2-OS cells without ciHHV-6 in them, just activated by the supernatant signal.

Also, as others were saying above (I think) the pSILAC analysis was performed only on ciHHV-6 U"-OS cells, I think(?). Did they analyses the levels of all proteins in the cells and then only show the ones associated with mitos? I don't clearly see all the elements they state were most notably altered, in the abstract (but random protein/enzyme names, eh?):

Expressed levels of many mitochondria associated proteins (enzymes) where changed, as measured by pSILAC experiment (pulsed stable isotope labelling by amino acids in cell culture) some significant ones labelled in [Fig1 of paper]:

I don't think ME involves serious long-term cellular damage.

Well, not *just* that, for sure. But factors that cause damage (toxins, etc) could also trigger ME/CFS. And damage (of at least some varieties) is more likely to accrue while in an ME/CFS state. This will pressumably limit one's maximum (good day) capabilities, when not crashing, or whatever.

I wonder if mitochondria have an internal timer, so that 21 days (or whatever) after they're created, they trigger a self-destruct sequence.

I don't think there's anything so precise... Turn-over's going to vary a lot by tissue, as Learner1 says, by an order of magnitude (fast in liver, for example). And also by one's activity and food intake, etc. Might be interesting to read up on if mitos have any kind of expiration time mechanism... I'd think that damage would be more likely a determining factor.

The ones my lab testing suggests I need:

So, basically *all* the anti-oxidants then? Lol! We're kinda going well off-topic, here, but have you ever noted a negative effect of these on muscle mass? They're supposed to reduce/block the hormesis effect of muscle damage from exercise/exertion that builds them up. Vit-E I know's been associated with raised cancer risk (in people with smokng DNA damaged lungs). But perhaps your body's producing so much more ROS, neither of these are likely to be an issue?

Where's this image from...?

the black stuff here which is arsenic:

 

[ZeroGravitas]

Cort just published a great write-up on a paper from November 2019 by lead author Nuno Sepúlveda [SimmaronResearch]. Full paper text here [NCBI].

"ME/CFS as a Hyper-Regulated Immune System Driven by an Interplay Between Regulatory T Cells and Chronic Human Herpesvirus Infections"

Previously posted about here on [PhoenixRising], with no discussion as yet. Here on [s4ME].

This seems really promising to me, like it might tie in closely with Prusty's work, discussed in this thread.

It seems like it might give an explanation for how sustained partial reactivation of HHV-6 could happen. Also in HSV-1 and EBV. I've not read it through, yet, but this table of information seems quite relevant, here, it describing which cells they think HHV-6 (and the other viruses) infect and then are latent in (mostly immune system cells... ):

 

[ZeroGravitas]

Oh, just stumbled back over this bit of info I posted about mitochondrial forms (back in Phair's thread). Handy here (I probably should include the diagram in the summary or something, higher up):

I've not been able to find Naviaux or anyone explicitly state that fussed mitochondria are more chemically efficient at producing ATP, or such. But the fussed state does seem associated with higher energy demands and aerobic production, fragmented with resting state, gycolosis and mt breakdown. e.g. this 2012 paper. (Also long membrane structures transmitting electrical charge deeper into cells where there's less oxygen, etc.)

Mitochondrial fragmentation is a response to cell danger (also pre-empts apoptosis, etc). Apparently a strategy of avoiding putting all one's eggs in the same basket, in terms of preserving some functional mtDNA. When they fuse again, functional DNA is shared, restoring function to the bodies with damaged/missing enzyme DNA. (So higher overall energy output fused than fragmented.)

Mitochondria with functional DNA are then (hopefully) selected for. mtDNA is entirely lost, fairly rapidly, if the fusion process is blocked. Mitochondria are recycled (in the lysome) and renewed on a time scale of a few days. Fragmentation/fusion happens over the course of hour(s).

What's interesting is that the fused mitochondrial networks also act like power lines, allowing a flow of electrons (or protons? I forget, meh), from the ends that are close to the cell membrane, where oxygen is more accessible, down into the depths of the cell. So relying less on oxygen diffusion. Don't have a reference for that off-hand.

 

[Learner1]

Yes, there seems to be some good synergy between the 2 papers. These are exciting developments.

I'm interested in how much oxidative and nitrosative stress are caused by fragmented, fused, or dynamic mitochondria make. Have you found any more information on that?

So, basically *all* the anti-oxidants then? Lol! We're kinda going well off-topic, here, but have you ever noted a negative effect of these on muscle mass? They're supposed to reduce/block the hormesis effect of muscle damage from exercise/exertion that builds them up. Vit-E I know's been associated with raised cancer risk (in people with smokng DNA damaged lungs). But perhaps your body's producing so much more ROS, neither of these are likely to be an issue?

Yes, but I need different amounts of each. The antioxidants work together as part of an antioxidant network, a term coined by Lester Packer the leading antioxidant researcher at UC Berkeley.

Taking a single antioxidant can be a recipe for disaster, as you've pointed - they need to be balanced do that antioxidants get used and become pro-oxidants, they can be recycled back to antioxidants by their companion antioxidants.

I haven't noticed any changes in muscle mass, but a few months ago, I researched protecting my body when I needed to have a CT scan and took double my usual amount of ALA, A, C, E, resveratrol, CoQ10, and astaxanthin. I went for a walk that day and had an amazing amount of energy, easily going up a slight hill I can have trouble on and RUNNING across a street at the end of my walk , something I never do.

It was clear that my body really needs the antioxidants my tests always say I'm depleted in. S little more investigation showed me that A, E, and ALA, specifically, gave me more energy, which I found interesting, as I'd always focused more on C and glutathione.

I seem to have runaway oxidative stress, which has been found by several ME/CFS researchers, in concert with nitrosative stress. It damages cell membranes through lipid peroxidation and damages DNA - there's a marker, 8OH-dG, which shows this. My increased antioxidants 4ecebtky hit my 8OH-dG down to zero, but lipid peroxides are still high, so I'm investigating. I think nitric oxide, or lack of it, is also playing a role. Given how far I've come, by shutting down my viruses and improving my mitochondria, I'm hoping that if I can get this extraordinary oxidative stress under control, tgstveikl allow me to say I'm cured...until then, on with the adventure...

Where's this image from...?

I got it from Kendall Wallace, a researcher in mitochondrial toxicity, who presented it at the 2016 United Mitochondrial Disease Foundation Conference I went to. One day of the conference was all about mito toxicity. Other stuff gets into mitos too and clogs them up or damages the inner membrane, compromising ATP production.

The image made a big impact on me, as that same week, after detoxing for about 4 years and looking pretty clean, I'd collapsed after being given IV PokyMVA, a lipoic acid polymer, which usually helps energy. My labs came back showing acute arsenic toxicity, where arsenic hadn't really ever shown up on my metals tests. Turns out it was sequestered in my mitos and released with the ALA! The image very graphically showed me what was going on. I eventually got rid of the arsenic, which gave be more energy.

 

[ZeroGravitas]

how much oxidative and nitrosative stress are caused by fragmented, fused, or dynamic mitochondria

No idea of relative numbers, sorry. Just know that Naviaux describes the M1 (fragmented) mitochondria as set up do deliberately produce ROS, with reduced use of oxygen almost as a side effect (to free up the oxygen for making the toxic defensive oxidants).

Taking a single antioxidant can be a recipe for disaster, as you've pointed - they need to be balanced do that

Nothing's ever straight forwards around here, is it...? Is there even a one size fits all rule of thumbs for the supplemenation ratios? Or does one really need to test? (I took one pass at testing *everything*, 6 years back, but it would be a ***** trying to access all that again now, for me, in the UK.)

It makes me wonder about MyHill pushing vit-C megadosing (to bowel tolerance). Other's too, specifically for (covid) viral infection, etc. Too much of a good thing...?