Ron Davis: Preliminary data shows problems with energy metabolism

[JaimeS]

when it is ready to be published will you please (pretty please) enter the 'Dance your PHD' contest?

http://www.sciencemag.org/news/2015/11/announcing-2015-dance-your-phd-winner

OMG I'd collapse

 

[dannybex]

So we know that its a mitochondrial problem but whats seems to be missing to me is why the bacteria, virus, parasite or autoimmune response cause it?

It could be due to things like elevated levels of ammonia (just as one example) as a result of an infection.

From this study:

"It is also possible that an initial slight to moderate increase in brain ammonia concentration by parasite's glutamine catabolic processes impairs the Krebs cycle, probably via inhibition of key metabolic enzymes like α-ketoglutarate (αKG) dehydrogenase (Cooper and Plum, 1987) and electron transport chain enzymes (Qureshi et al., 1998). Furthermore, the carbon needed to detoxify the excess parasite-derived ammonia depletes α-KG from cells, thereby additionally affecting the Krebs cycle (Ott et al., 2005)."

(etc., etc.)

"The lactic acidosis observed in CM may thus be largely due to ammonia-induced crippling of Krebs cycle and switch to the lactate producing glycolytic pathway."

 

[msf]

They don't say they are - it would be nice if they did. The refer to commercial and custom technologies. These may or may not be externally validated and recognised as such. If not - who knows what they mean if anything. I'm not trying to deliberately critical but it's an important point.

Sure, but hopefully it´s one Davis is aware of.

 

[greeneagledown]

@Jonathan Edwards -- Were you present for Ron Davis's presentation, and if so, do you have any thoughts on his very preliminary findings?

 

[MEMum]

If my eyesight was right, the really low metabolite of the TCA cycle was 2,3 diethyl succinate. Not sure if that's useful info to anyone.

 

[Jonathan Edwards]

@Jonathan Edwards -- Were you present for Ron Davis's presentation, and if so, do you have any thoughts on his very preliminary findings?

I have to admit to being puzzled here. Ron Davis gave two presentations to the IiME colloquium and I am not aware that he presented any data in either of these. I may have lost concentration but there was no discussion I was aware of about new data. I was not present when he presented at the Friday conference. It is more usual for people to present data at the colloquium and not at the conference, because the colloquium material is treated as confidential if presenters ask for that. I have yet actually seen the data that are being discussed here in the form of raw data so I find it hard to comment.

 

[alex3619]

Let me highlight that an important point of Martin Pall's peroxynitrite hypothesis is damage to mitochondrial function.

 

[Justin30]

It could be due to things like elevated levels of ammonia (just as one example) as a result of an infection.

From this study:

"It is also possible that an initial slight to moderate increase in brain ammonia concentration by parasite's glutamine catabolic processes impairs the Krebs cycle, probably via inhibition of key metabolic enzymes like α-ketoglutarate (αKG) dehydrogenase (Cooper and Plum, 1987) and electron transport chain enzymes (Qureshi et al., 1998). Furthermore, the carbon needed to detoxify the excess parasite-derived ammonia depletes α-KG from cells, thereby additionally affecting the Krebs cycle (Ott et al., 2005)."

(etc., etc.)

"The lactic acidosis observed in CM may thus be largely due to ammonia-induced crippling of Krebs cycle and switch to the lactate producing glycolytic pathway."

Just throughing this out their but through testing I know of a couple people that did not have high ammonia in serum. I dont know if thisbtranslates to the brain.

I really like this hypothesis and know that certain Drs believe this ispart of the problem.

Something in the gut seems to perpetuate or keep the disease going.

 

[Justin30]

Let me highlight that an important point of Martin Pall's peroxynitrite hypothesis is damage to mitochondrial function.

I agree but woud want to see a large fishing study using PET and SPECT Scans to rule out damage to the small vessels in the brain...whether it is hyperporfusion, low blood flow etc.....

Further like in every thread I keep say encephalomylietis and Autonomic Dysfunction is one of the main symptoms of Mito Diseases.

 

[Kati]

I agree but woud want to see a large fishing study using PET and SPECT Scans to rule out damage to the small vessels in the brain...whether it is hyperporfusion, low blood flow etc.....

Further like in every thread I keep say encephalomylietis and Autonomic Dysfunction is one of the main symptoms of Mito Diseases.

I agree, brain imaging is much needed including replication from the Japanese study.

 

[BurnA]

I have to admit to being puzzled here. Ron Davis gave two presentations to the IiME colloquium and I am not aware that he presented any data in either of these. I may have lost concentration but there was no discussion I was aware of about new data. I was not present when he presented at the Friday conference. It is more usual for people to present data at the colloquium and not at the conference, because the colloquium material is treated as confidential if presenters ask for that. I have yet actually seen the data that are being discussed here in the form of raw data so I find it hard to comment.

In terms of data, what I remember is Ron presented the top 10 substrate outliers in terms of being excessive and deficient. I am not sure if this was based on Whitneys results or a combination of the 3 profiles they have tested.

 

[Tuha]

In terms of data, what I remember is Ron presented the top 10 substrate outliers in terms of being excessive and deficient. I am not sure if this was based on Whitneys results or a combination of the 3 profiles they have tested.

did he say when they will present the data from the study to the wider public or when they are ready for publication?

 

[Mij]

Further like in every thread I keep say encephalomylietis and Autonomic Dysfunction is one of the main symptoms of Mito Diseases.

And we are stuck between a rock and hard place because exercise helps one but not the other in our case.

From the mito action website:

• Special care/caution with virus infections
• Exercise (exercise has been shown to increase mitochondrial function)

 

[Justin30]

And we are stuck between a rock and hard place because exercise helps one but not the other in our case.

From the mito action website:

• Special care/caution with virus infections
• Exercise (exercise has been shown to increase mitochondrial function)

Amen but I believe if you read deeper on that website it discusses some are unable to exercise as the condition is severe and life threatening.

But all in all we are stuck inbetween a rock and a hardplace....

 

[Mij]

I like the term Mitochondrial Dysautonomia Perhaps we could incorporate this in our name somehow? Get rid of fatigue!

 

[MEMum]

I have to admit to being puzzled here. Ron Davis gave two presentations to the IiME colloquium and I am not aware that he presented any data in either of these. I may have lost concentration but there was no discussion I was aware of about new data. I was not present when he presented at the Friday conference. It is more usual for people to present data at the colloquium and not at the conference, because the colloquium material is treated as confidential if presenters ask for that. I have yet actually seen the data that are being discussed here in the form of raw data so I find it hard to comment.

IMHO Ron Davis was using a few examples of initial results on the first few patients tested to illustrate the types of results they can get, such as huge deficiencies of one intermediate in the TCA cycle.
My notes are incomplete, but another example was from branched chain amino acid metabolism where there was a significant increase in B hydroxy isovaleryl carnitine. The enzyme, 3 methyl crotonyl CoA carboxylase is the next ? step in this pathway and is biotin dependent. He said that one patient's health had been completely turned round on biotin. Not sure if this related to one of the 3 or so, very serious patients whose blood has been analysed yet or not.

The third pathway he mentioned was tryptophan metabolism. I think someone already posted this, but I'll add my info. Indolamine 2,3 dioxygenase was upregulated. This patient had an infection which upregulates the enzyme. From my notes, this took the tryptophan on a different pathway from the manufacture of melatonin or 5HT.

The last pathway was conversion of GTP to biopterin. I think he said GTP and BH4 ,both look low in PwME. (or it could be that GTP cyclohydrolase is low). BH4 is used in the production of serotonin and dopamine.

To reiterate, Professor Davis was not 'presenting data' in the 'these are the results of our study...'

Rather he was demonstrating the range of metabolic pathways the data will cover and a few of the major differences picked up so far.

Hopefully someone with more recent biochemical training can work out whether the above makes any sense @Simon,@ Jaimie etc.

 

[alex3619]

I like the term Mitochondrial Dysautonomia Perhaps we could incorporate this in our name somehow? Get rid of fatigue!

Yes, if the evidence stacks up over time that might be a good name.

 

[BurnA]

did he say when they will present the data from the study to the wider public or when they are ready for publication?

No, not that I remember. I know they had to develop software to analyse the data but no idea of the status of that.

Given the volume of data to be analysed i expect it to take some time, but i don't know.
The main thing is that Ron Davis is just as eager as we are for results so I am sure he is moving things along as fast as possible.

 

[Sushi]

Further discussions as to why this might be, with Marty Pall and Rich van Konyenburg, led to Rich becoming very interested in glutathione, a path I was very much into at the time, given how it can severely impact mitochondrial function.

I have saved some of Rich's comments (both personal ones from emails and posts on various forums) and I had a quick look for some of them today. He analyzed the Kreb cycle results of a host of ME/CFS patients and found a repeated pattern. I'll paste in what I found quickly and look for more later. Here he is explaining some of the things he looked at:

I look to see is whether there is evidence for glutathione
depletion, because glutathione depletion would explain why there is a problem in
B12 utilization. The best place to look is in the citric acid cycle
metabolites. If citric acid (number 20) is high relative to the the first or
second ones that come after it, i.e. cis-aconitic or isocitric acids, that
suggests that glutathione is depleted when averaged over all the cells in the
body,

And:

Dysfunctioning mitochondria present a lower demand for oxygen (unless they are decoupled, in which case they produce a lot of heat, but this is not observed in ME/CFS, in which the peripheral body temperature is usually lower than normal, rather than higher). The dyfunctional mitochondria also produce ATP at a lower rate. ATP is needed to power muscle contraction. If it is being produced at a lower rate, the person is not going to be able to walk as fast for a sustained period of time. This accounts for the lower preferrred walking speed.

The inefficiency in oxygen utilization is explained by the fact that because the mitochondria are dysfunctional in the skeletal muscles in ME/CFS, the person has to rely more on anaerobic metabolism to produce their muscle ATP. This produces lactic acid, which must be sent to the liver for reconversion to glucose, via the Cori cycle. The liver, which does not have dysfunctional mitochondria, because it has a complete transsulfuration pathway and can thus convert methionine to cysteine to maintain its glutathione level, has to use oxygen to do this. This cycle is a much less efficient way to produce ATP than the normal oxidation of glucose by the mitochondria.

http://forums.phoenixrising.me/inde...king-rafferty-marshall-2009.7322/#post-145298

 

[Sushi]

More from Rich Van Konynenburg re: the Krebs cycle:

I analyze a lot of CFS cases, and frequently receive the results of urine organic acids tests and urine amino acids tests. Both of these types of tests have markers for B6, and I frequently find that PWCs are low in B6.

I suspect that the reason for this is that PWCs have to use amino acids as fuel to a greater degree than normal, healthy people, because the partial block early in the Krebs cycle interferes with the normal use of carbs and fats for fuel. B6 is used in the transamination reactions that convert one amino acid to another, which is necessary to feed them into the Krebs cycle beyond the partial block. I think that the heavy use of B6 (which is a coenzyme, which is not used up directly as a reactant) causes it to be degraded more rapidly than normal.

In my hypothesis, PWCs are not able to burn carbohydrates and fats
for fuel to make ATP very efficiently, because these fuels must enter
the Krebs cycle at acetyl-CoA, and there is a partial block shortly
beyond that, at aconitase. Amino acids from protein breakdown, on
the other hand, are able to enter the Krebs cycle at points beyond
this partial block. The muscle cells in a PWC therefore tend to burn
amino acids for fuel more than those in a normal, healthy person's
body.

I believe that the partial Krebs cycle block occurs because of the depletion of
glutathione. This allows the concentration of reactive oxygen species, which
are normally generated as part of the metabolism in the mitochondria, to rise.
They react with aconitase, one of the enzymes near the "beginning" of the Krebs
cycle and inactivate it by removing an iron ion. This places a partial block in
the Krebs cycle. The evidence that this occurs in CFS comes from urine amino
acids testing on PWCs, which frequently shows that the metabolites near the
beginning of the Krebs cycle are elevated, while alpha ketoglutarate is often
lowered. The reactions that can cause this are well described in the
biochemical literature.

If the glutathione levels can be restored, I believe that aconitase will be
restored and the partial block will be removed.