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Pyruvate Dehydrogenase Deficiencies and Cures?

debored13

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i'm just a layperson but the concept of mitochondrial toxicity seems complicated... wouldn't it generally depend on the metabolic pathways? something that might be toxic to the mitos might not be in someone else...
DNP is an exception that I can think of off the top of my head
 
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I mean pushing the mitochondria to run faster when they may not be in the best shape may be counterproductive.

The production of ATP throws off superoxide radicals, and if you don't make enough superoxide dismutase to defang them and peroxynitrites are created you can accrue damage to mitochondrial membranes and DNA.
thanks for the pubs @Learner1 I hadnt come across NTFactor. I will have a look over.........
 
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yeah this is a great list and i've only just started on it. Could you guys list supplement, especially powder supplement sources? i don't know which to trust...
@Hip devoted a few posts to sourcing reliable supplements in this thread

However, a number of studies have found that many companies selling supplements online are either incorrectly synthesized, incorrectly formulated, contain undeclared contaminations and impurities or are not present at the indicated dose. For example, one study found that only 2/12 companies sold supplements having no detectable substitutions or undeclared contaminants and fillers (Newmaster et al. BMC Medicine 2013, 11:222)

Its a minefield!
 

debored13

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@Hip devoted a few posts to sourcing reliable supplements in this thread

However, a number of studies have found that many companies selling supplements online are either incorrectly synthesized, incorrectly formulated, contain undeclared contaminations and impurities or are not present at the indicated dose. For example, one study found that only 2/12 companies sold supplements having no detectable substitutions or undeclared contaminants and fillers (Newmaster et al. BMC Medicine 2013, 11:222)

Its a minefield!
damn. i wonder how much that applies to suppliers of supplements that are bulk powders. it seems easier to put bullshit in a capsule than to fake a bulk powder. for ex., I know what theanine tastes like and it's consistency--it would be tough to fake that
 

pattismith

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I @pattismith I also came across the mito tox table (you pasted above) while trawling the internet for mito-toxins. But I dont trust the list because they dont provide references/sources or any reasons for the proposed mechanisms. In some cases they incorrectly interpret a drug as being toxic when in fact, depending on the context, can be therapeutic (eg metformin). Do you know where to find a properly referenced list of mitochondrial toxins? I cant seem to find one...

Rodger
I do trust this site which is a reference for mito diseases, but I agree with you, the list is not perfect, in fact some mitotoxic drugs are just... missing...:)

You have to keep in mind that it is often a dosage questions, some drugs are safe at a low dosage, mito inhibitors at a higher dosage, and cause mito damages at higher levels.

Drugs that target cancer are usually used at high dosage and have sometimes mutagen activities which lead them to be highly mito-toxic.

Mitochondrial dysfunctions will increase the sensitivity to these mito-toxic drugs, this means a lower dosage can be toxic.

In this other site for mitochondrial diseases patients, you will find a more subtile list.(some sources are quoted)

You can see that Paracetamol can be toxic as well as Aspirin.

In fact, when I started monitoring my blood lactates levels, I noticed that taking only a small dose of Alka seltzer (Aspirine + sodium bicarbonates) was producing an unexpected rise.

It was 6 months ago now when I realized this, and I have learn a lot on mitochondrial toxicity since then.
 

pattismith

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damn. i wonder how much that applies to suppliers of supplements that are bulk powders. it seems easier to put bullshit in a capsule than to fake a bulk powder. for ex., I know what theanine tastes like and it's consistency--it would be tough to fake that
Yes, the problem of supplements when we look for quality quickly becomes a money problem.

It is especially acute with some supplements like Ubiquinol. If you are looking for digestible form, the price is rising accordingly.

I found a form in my country that seems to work, and I currently take 400 mg a day, and it is a big part of my supplements budget.
 
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I do trust this site....
In this other site for mitochondrial diseases patients, you will find a more subtile list.(some sources are quoted)
.
Hi @pattismith the above list also doesnt give specific references for specific drugs......

Even the biochemical basis for how a drug is determined as being a mitochondrial toxin is not clear from the list. For example, doxorubicin is included on the above list of mitochondrial toxins. But doxorubicin is a topoisomerase inhibitor that primarily causes DNA damage resulting in the activation of a nuclear DNA damage response including p53 activation. It is known that doxorubicin is not a specific mitochondrial toxin because mitochondrial metabolism in cells that lack p53 is completely unaffected by doxorubicin. Also, mitochondrial metabolism in cells lacking nuclei is unaffected by doxorubicin. Thus, doxorubicin is not a mitochondrial toxin. What doxorubicin does is kill cells and mitochondrial shutdown occurs during the death process along with a myriad of other biochemical events. If doxorubicin is classed as a mitochondrial toxin, then any chemical that can kill a cell while causing secondary mitochondrial shutdown would be classed as a mitochondrial toxin. Thus, the scientific criteria of what constitutes a mitochondrial toxin is important.

I guess many of us with CFS are trying to sort out 'mitochondrial fitness' and what treatments/drugs may decrease 'fitness' (which we would avoid) and what treatments/drugs may increase 'fitness' (which we might consider taking). A good evidence based list would be really helpful but so far I havent been able to find one.

What is really fascinating though is that some antibiotics (not all) have been clearly shown to impair mitochondrial metabolism (I reserve the term 'mitochondrial toxins' to compounds such as mustard gas). The reason why some antibiotics impair mitochondrial metabolism is fascinating. Mitochondria were originally derived from bacteria. Some of the same fundamental biochemical processes that antibiotics target in bacteria have remained conserved in our mitochondria for millions of years and so are affected by the same antibiotics. Amazing!

Anyway, there a so many internet sites that claim to provide genuine scientific information that is claimed to be sourced from scientific publications but the level of scientific backing is often lacking........ It makes it a nightmare to find reliable information and not 'crash' in the process.

I'll keep looking

Rodger
 
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pattismith

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@rodgergrummidge , good point!

Sorry if I am not able to do the job, as you say "It makes it a nightmare to find reliable information and not 'crash' in the process."
(I actually read the Doxo publications before answering you, and I feel exhausted, I don't thank you :lol:)
 

Learner1

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@rodgergrummidge On day 4 of the 2016 United Mitochondrial Disease Conference in Seattle, there were 2 presentations regarding drugs and mitochondrial toxicity.

Days 1-3 of the conference explained how mitochondria work, what can go wrong, how they can be repaired, etc. It was at a level of researchers talking to doctors.

The Day 4 presentations explained how they're building a database of drugs and substances that are toxic to mitochondria.as I've had a good deal of brain fog between them and now, I can't remember the gory detail.

The salient points I recall are:
  • It's a large database, named with a clever acronym, built over several years.
  • 75% of drugs they tested were toxic to mitochondria, and they'd tested a lot
  • The mechanisms of toxicity varied and should be in the database
  • I think at least some of them were from University of Minnesota but I think they were from different institutions
  • Robert Naviaux (who'd been the first speaker of the day) got up in the QA session afterward and gave a very passionate, off-the-cuff speech imploring doctors in the audience to become advocates for less toxicity and to be extremely cognizant of what they were prescribing patients, as they could inadvertently harming their patients with some of these drugs.
Sorry I can't remember more. But It was concerning. Perhaps you can dig up more info.
 

Mary

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my problem with keto is simply I don't have great digestive enzymes and have been a vegetarian for most of my life
Besides being low in digestive enzymes, you might also be low in stomach acid and need to take betaine HCL with pepsin. Many of us here are low in stomach acid, and if you go on a keto diet, you will really need your stomach acid to be up to par because digesting lots of protein and fat takes lots of stomach acid.

A simple test to check stomach acid is to dissolve 1/4 teaspoon baking soda in 8 ounces of water and drink it on an empty stomach. If you don't burp within 2 minutes, it indicates low stomach acid.

I found a long time ago that digestive enzymes alone weren't enough, I needed the betaine HCL with pepsin. The pepsin is important for digesting protein.
 
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@rodgergrummidge , good point!

Sorry if I am not able to do the job, as you say "It makes it a nightmare to find reliable information and not 'crash' in the process."
(I actually read the Doxo publications before answering you, and I feel exhausted, I don't thank you :lol:)
we all love and appreciate your contributions..... by sharing the load we share the effort..... and so we help share what little energy we have to understand this terrible disease.....
 

debored13

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Yes, I've made a great deal of improvement in working all of this. I was sleeping 16 hours a day and brain fogged and unable to think or do much with PEM and POTS, but now I sleep 8 to 9 hours a day, am clear headed most of the time, PEM is more rare, POTS is improving.

I've attacked this on multiple fronts. First, replenishing nutrients I was deficient in. My body uses huge quantities of B vitamins, antioxidants, lipids and amino acids. And working on my gut - I had no lactobacillus or bifidobacteria.

Then, working on my hormones and normalizing my sleep. I take thyroid, hydrocortisone, pregnenolone, progesterone, DHEA, and testosterone. And a sleep cocktail of aminos, magnesium, B6, etc.

Then, attacking infections, first holistically, and then after figuring out my immune system was broken, with LDN, antivirals, antibiotics, high doses of vitamin C, and oxygen therapies. I also get IV immunoglobulins to help and to work on the autoimmune antibodies causing POTS caused by the infections and am considering 10 Pass oxygen and Rituximab.

And I'm on a low carb, Paleo diet and exercise carefully, lifting weights and walking, to promote mitochondrial biogenesis.

It's a lot, but it's all helping. I found the attached model of treating CFS and found it helpful in explaining my abnormal lab results and the approach my doctors are using to help me - I have problems in every box in the chart.

Good luck in figuring out where you need to go in seeking a solution. This is a multi headed beast.
what dose do you take the pregnenolone at?
 

garcia

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Ethyl pyruvate has been on my radar since last year. Someone on reddit (presumably healthy) posted that they took a supplement which had Ethyl pyruvate as the main ingredient and got amazing cognitive improvements from it. Sadly that supplement is no longer available, and the only other sources I can find are research suppliers.

I'd also like to try a non-calcium based source of regular pyruvate (doesn't have to be ethyl), just because whilst I do well with pyruvate, I don't do well with calcium, and all the pyruvate supplements seem to be calcium pyruvate. Pyruvate is one of the few mito boosters that actually does what it says on the tin.
 

debored13

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Ethyl pyruvate has been on my radar since last year. Someone on reddit (presumably healthy) posted that they took a supplement which had Ethyl pyruvate as the main ingredient and got amazing cognitive improvements from it. Sadly that supplement is no longer available, and the only other sources I can find are research suppliers.

I'd also like to try a non-calcium based source of regular pyruvate (doesn't have to be ethyl), just because whilst I do well with pyruvate, I don't do well with calcium, and all the pyruvate supplements seem to be calcium pyruvate. Pyruvate is one of the few mito boosters that actually does what it says on the tin.
I saw the reddit post haha! they said that there used to be an energy drink with ethyl pyruvate in it. I'm gonna wait and maybe try it with doctor supervision though. Some of these supplements are more mild and have a lot more anecdotal evidence of safety, but I learned my lesson with taking a high dose of pregnenolone.
 

debored13

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A user named Travis, on another forum, made this post in response to my questions about treating the issues with pyruvate dehydrogenase in ME/CFS directly. It's a tiny bit above my head, but I remember reading Szent-gyorgyi's work "cancer and the living state" and him talking about methylgloxal as possibly really important for the formation of life on earth, and having an important role in protein conductivity/the redox aspects of the living state. So now I want to go back and read that and refresh myself, anyway, here's the post:


"I can't think of anything besides thiamine, unless of course you'd find a way to increase the expression of the enzyme. Yet there could be a way to do this: Since pyruvate dehydrogenase is under negative regulation by hypoxia inducible factor-1—via transcribing-for pyruvate dehydrogenase kinase—then taking baicalein and/or lapachol should ultimately act to increase it. These phytochemicals are the two most powerful natural glyoxalase-1 inhibitors (Kᵢ ≈ 5–7 μM), acting to increase methylglyoxal by inhibiting its degradation to lactate. Methylglyoxal is very powerful because it selectively reacts with exposed arginyl side-chains on proteins, irreversibly converting them into hydroimidazolone rings. By reacting with 'hot spot' arginine residues is how methylglyoxal been shown to regulate transcription (Yao, 2007), and the transcription factor HIF-1 is also inactivated in this manner (Bento, 2010). Taking a glyoxalase inhibitor such as baicalein could be expected to: increase intracellular methylglyoxal, decrease intracellular lactate, inhibit 15-lipoxygenase (Deschamps, 2006), inactivate hypoxia inducible factor-1α (Bento, 2010) thereby increasing pyruvate dehydrogenase expression. Methylglyoxal had acquired a pathological reputation because it reacts with extracellular proteins in diabetes, yet this only occurs in states where glucose cannot get into the cell where it belongs. Methylglyoxal also forms inside the cell mainly from carbohydrates, and appears to be the biochemical signal for their metabolic rate. Intracellular methylglyoxal has also acquired reputation for powerfully inhibiting cancer, and very likely the reason why baicalein and lapachol have been so successful at treating it.



Kim, Jung-Whan. "HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia." Cell metabolism (2006)



'Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1a null cells increases ATP levels, attenuates hypoxic ROS generation, and rescues these cells from hypoxia-induced apoptosis. These studies reveal a hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production.' ―Jung-Whan



Bento, C. F. "The chaperone-dependent ubiquitin ligase CHIP targets HIF-1α for degradation in the presence of methylglyoxal." PloS one (2010)



'Methylglyoxal has recently been shown to modify HIF-1α on arginine residues [22], probably leading to changes in protein conformation. Indeed, immunoprecipitation experiments showed that methylgloxal-modified lysine and arginine residues of HIF-1α, increasing its immunoreactivity against N-carboxymethyl-lysine and Nα-acetyl-Nδ(5-hydro-5-methyl)-4-imidazolone (MG-H1) antibodies, respectively. Thus, we hypothesized that modification by methylgloxal might stimulate proteasome-dependent degradation of HIF-1α, as a result of post-translational modifications.' ―Bento



Yao, Dachun. "High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A." Journal of Biological Chemistry (2007)



'Our studies demonstrate for the first time that methylglyoxal causes post-translational modification of a coregulator protein and that this modification affects gene expression. The extent of this modification reflects the net effect of a variety of intracellular processes, including metabolic flux and reactive oxygen formation, and may thus function as a new integrating signal to coordinately regulate distinct patterns of gene expression.' ―Yao"
 

debored13

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Human African Trypanosomiasis (HAT) also called sleeping sickness is an infectious disease in humans caused by an extracellular protozoan parasite. The disease, if left untreated, results in 100% mortality. Currently available drugs are full of severe drawbacks and fail to escape the fast development of trypanosoma resistance. Due to similarities in cell metabolism between cancerous tumors and trypanosoma cells, some of the current registered drugs against HAT have also been tested in cancer chemotherapy. Here we demonstrate for the first time that the simple ester, ethyl pyruvate, comprises such properties.