The itaconate shunt hypothesis

Hutan said:
perhaps there are particular conditions that increase the proportion of cells that secrete IFN. I guess also, there might be differences in the number of IFN receptors, so there might be differences in the sensitivity to a given level of IFN.
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See new preprint from the Cleveland Clinic: Inflammatory Cytokines Can Induce Synthesis Of Type-I Interferon (2024, Preprint: BioRxiv)

The observations, reported here, indicate that IFN-β can be induced by the RLR pathway without any participation of viral or cellular RNA. Such induction requires PACT to be activated by p38, a MAPK, that is activated by many extracellular stimuli including inflammatory cytokines. But RIG-I could bind to PACT only if it was primed. Both proteins needed specific modifications before their interaction; PACT needed to be phosphorylated and RIG-I needed to be dephosphorylated. Further investigations should reveal the nature of physiological cues that lead to RIG-I priming. PACT activation by p38, on the other hand, can happen in response to a variety of extracellular stresses as observed for PKR activation by PACT.
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Merged thread

Itaconate Trap Study

STUDY AIM
This project aims to look at metabolic traps in central carbon metabolism that lead to observed altered energy production pathways in ME/CFS.

LEAD INVESTIGATORS
Christopher Armstrong, PhD
Rob Phair, PhD

UPDATES AND POTENTIAL
  • Constructed the differential equation model for the TCA cycle.
  • Developed the itaconate trap hypothesis by looking for mechanisms that prioritise the use of amino acids for energy production.
  • Itaconate cycle can be initiated by pathogens specifically via innate immune signals (IFN-alpha).
  • Currently exploring the relationship between IFN-alpha, itaconate, cellular metabolism, and ME/CFS.

STUDY HYPOTHESIS AND DESCRIPTION
One of the key metabolic theses aiming to explain ME/CFS symptoms is the dysregulated nitrogen metabolism theory proposed by Armstrong and colleagues. Three features of this theory make it attractive:

1) it is consistent with the observed shift from carbohydrate to alternative sources of energy (amino acids and fatty acids),

2) it predicts a reduction in oxygen consumption consistent with a hypometabolic state, and

3) it predicts overproduction of ammonia, a known neurotoxin that could explain ME/CFS neurological symptoms. One underdeveloped aspect of the nitrogen metabolism theory of ME/CFS is the mechanistic chain of events connecting the initial infectious or traumatic trigger to a chronically altered state of central carbon and mitochondrial metabolism.

This computational proposal aims to fill that gap by testing mechanisms that have the potential for switch-like or bistable behavior.

Objectives
  • Explore the itaconate trap and other potential traps in central carbon metabolism.
  • Build pathways of central carbon metabolism.
  • Develop kinetic models to try predict potential “weakness” points.
  • Test the hypothesis experimental

https://www.omf.ngo/itaconate-trap-study/
 
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John Mac said:
it is consistent with the observed shift from carbohydrate to alternative sources of energy (amino acids and fatty acids),

2) it predicts a reduction in oxygen consumption consistent with a hypometabolic state, and
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I’m not sure to what extent this finding has been replicated, which gives me some concern.

However, I know @chillier has done some analysis of published data that, I believe, is consistent with the finding. Maybe they can comment?
 
Simon M said:
I’m not sure to what extent this finding has been replicated, which gives me some concern.

However, I know @chillier has done some analysis of published data that, I believe, is consistent with the finding. Maybe they can comment?
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Reductions in oxygen consumption have been reported in isolated PBMCs. This is what Thomas et al 2020 reported and was the trend reported by Fisher, Missailidis et al 2020 in lymphocytes (not significant, and also no plate technical replicates from what I can tell). In long covid reduced oxygen consumption rates were reported in Guo et al 2023 discussed here but with small sample sizes. I'm sure this has been done in other papers too, I have some recollection of Maureen Hanson's group looking at this. I wouldn't say I've seen anything that has convinced me this finding is solid yet - it's also been pointed out that PBMCs in circulation are not doing much, so are metabolically inactive sort of by definition.

In the experiment we are replicating from Fluge et al 2016, they see the opposite phenotype - an increased oxygen consumption rate. The experimental set up is different though, instead of isolating PBMCs they isolated patient serum and applied it to cultured (normal/healthy) cells.

So we don't know what is really happening all together in vivo. Maybe the serum is encouraging the cells to behave in a certain way, and when the cells are isolated (from the serum) they no longer are receiving that signal, but are now in poor condition (perhaps from increased ROS from increased respiration) and therefore respiration rates are reduced - total speculation.
 
As for a preference for amino/fatty acids as substrates for aerobic respiration, this was also argued in Fluge et al 2016: Lower levels of certain serum amino acids which may be used to replenish TCA cycle intermediates were observed, as well as higher transcript levels of genes involved in inhibiting the activity of pyruvate dehydrogenase (important for glucose based aerobic respiration). I'm not really sure about the amino acid findings because differences in these amino acids are not often detected in other metabolomics papers on plasma.

There was a paper from Hanson's lab Maya et al 2023 where they argued increased fatty acid utilisation in isolated lymphocytes (just significant p=0.04). This was done by measuring oxygen consumption as previously and seeing how it changed when using an inhibitor of a protein essential for fatty acid oxidation.
 
@MelbME it is good to have you here. I am a mother or a teen with severe ME and my grasp on the science is basic so if you do reply please do so in layman’s terms. My understanding of the Itaconate Trap theory is that it allows for a steady disease state that can be impacted further with PEM crashes. What is the hypothesis for what happens in recovery from PEM to the previous baseline? And conversely, why might there be a longterm (hopefully not permanent) reduction in baseline? Or to put it another way - why do some go from Severe to Very Severe long term?
 
Deanne NZ said:
@MelbME it is good to have you here. I am a mother or a teen with severe ME and my grasp on the science is basic so if you do reply please do so in layman’s terms. My understanding of the Itaconate Trap theory is that it allows for a steady disease state that can be impacted further with PEM crashes. What is the hypothesis for what happens in recovery from PEM to the previous baseline? And conversely, why might there be a longterm (hopefully not permanent) reduction in baseline? Or to put it another way - why do some go from Severe to Very Severe long term?
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We've observed a push towards amino acids being used for ATP in a few studies (us and collaborators) and others have shown the same, anyone that has bothered to look has found the same. Typically sugar or fat is used for ATP production. This elevated use of amino acids in ME patients is noteworthy.

The initial identification of the itaconate shunt came about from looking at mechanisms in ATP production that could prompt this elevated use amino acids for ATP production in ME patients. Especially we were interested in mechanisms linked to infection or inflammation. Itaconate shunt hypothesis does this.

It's very interesting biology. In terms of projecting how it creates PEM, this is possible from many angles but there really isn't much biological characterisation of PEM. This an area of most urgent need and a number of groups (including ours) have data coming out soon. PEM at the cellular level is without evidence, PEM as far as we know occurs at the full system level.
 
MelbME said:
We've observed a push towards amino acids being used for ATP in a few studies (us and collaborators) and others have shown the same, anyone that has bothered to look has found the same. Typically sugar or fat is used for ATP production. This elevated use of amino acids in ME patients is noteworthy.

The initial identification of the itaconate shunt came about from looking at mechanisms in ATP production that could prompt this elevated use amino acids for ATP production in ME patients. Especially we were interested in mechanisms linked to infection or inflammation. Itaconate shunt hypothesis does this.

It's very interesting biology. In terms of projecting how it creates PEM, this is possible from many angles but there really isn't much biological characterisation of PEM. This an area of most urgent need and a number of groups (including ours) have data coming out soon. PEM at the cellular level is without evidence, PEM as far as we know occurs at the full system level.
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Thank you!

When you say full system level, what do you mean by that? Every cell is affected?

Can you give us a little preview of what data will come out when?

Do you think there is direct or indirect evidence of tissue damage in ME/CFS?
 
MelbME said:
We've observed a push towards amino acids being used for ATP in a few studies (us and collaborators) and others have shown the same, anyone that has bothered to look has found the same. Typically sugar or fat is used for ATP production. This elevated use of amino acids in ME patients is noteworthy.
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Yes, very low levels of amino acids and omega 3 in my case despite eating a healthy diet. Low levels of antioxidants as well.
 
butter. said:
Thank you!

When you say full system level, what do you mean by that? Every cell is affected?

Can you give us a little preview of what data will come out when?

Do you think there is direct or indirect evidence of tissue damage in ME/CFS?
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Oh I just mean that we haven't shown that we can make individual cells experience PEM. It might be possible but it has not been shown. All we really know of PEM is clinical research of the patient function.

We have some data that we will submit to publication in next couple months, not sure when published. Have thought about preprints to help with delays. Urine samples over several days of a PEM event is what we have on that but only 10 people.

Major work to be published in this space in next 12 months. I'm involved in two studies comparing PEM samples to average day samples. One driven by Stanford (Snyder group) and one by us in Melbourne.
 
MelbME said:
Oh I just mean that we haven't shown that we can make individual cells experience PEM. It might be possible but it has not been shown. All we really know of PEM is clinical research of the patient function.

We have some data that we will submit to publication in next couple months, not sure when published. Have thought about preprints to help with delays. Urine samples over several days of a PEM event is what we have on that but only 10 people.

Major work to be published in this space in next 12 months. I'm involved in two studies comparing PEM samples to average day samples. One driven by Stanford (Snyder group) and one by us in Melbourne.
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Thank you again, Chris.

Your hypothesis seems to indicate that mitochondria are not functioning correctly, the obvious go to organelle, do you think we are dealing with damaged mitochondria or dysfunctional mitochondria, in the sense that mitochondria are actually not damaged but e.g. aberrant epigenetic control leads to dysfunction?
 
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butter. said:
Thank you again, Chris.

Your hypotheses seems to indicate that mitochondria are not functioning correctly, the obvious go to organelle, do you think we are dealing with damaged mitochondria or dysfunctional mitochondria, in the sense that mitochondria are actually not damaged but e.g. aberrant epigenetic control leads to dysfunction?
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My guess is regulatory disarray. Something in metabolism / signalling going wrong that has wide ranging knock-on effects that include changes to mitochondria
 
MelbME said:
It's an interesting question to ask, are all cells operating under the same altered condition? Is it just a tissue specific phenomenon? Is it 1 in every 100 cells of a tissue that drag the rest down?
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I have been considering that not all cells are affected the same for decades. This should be the default assumption in my opinion. However there are tissue types that show abnormal physiology, including immune cells and vascular endothelia. There are also differences in energy demand by various tissues.
 
butter. said:
Thank you again, Chris.

Your hypothesis seems to indicate that mitochondria are not functioning correctly, the obvious go to organelle, do you think we are dealing with damaged mitochondria or dysfunctional mitochondria, in the sense that mitochondria are actually not damaged but e.g. aberrant epigenetic control leads to dysfunction?
Click to expand...

I think mitochondria are functioning fine broadly, they are responding to something though. As @DMissa points out, they could be responding to a signal.
 
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