Research news from Bhupesh Prusty

Estherbot said:
FWIW he's reached his fundraising target.

https://uk.gofundme.com/f/gofundmecfs-support-scientific-research-mecfs

Being a tease on Twitter is an unusual way to break research news, especially as he needs to replicate and check his findings.

We've all had plenty of false dawns... We shall see....
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Yes, Prusty became quite active on Twitter when the fundraiser began. Not too sure what to think of it. As long as his findings are solid, I don't necessarily see him providing insights into his research as a "wrong" way to boost the fundraiser. But it's irresponsible of him if he knows his findings are not very meaningful, both for the financial aspect (donations coming straight from the pockets of people with ME) and for creating false hopes.

Now the NIH and Solve ME/CFS think that his research is serious, so I wouldn't think the latter holds. Still, we don't know that until his findings are peer-reviewed, published & replicated. So I'll go with cautious optimism, personally.

And let's hope his Twitter account doesn't go dead now that the fundraiser has met its goal.

EDIT: actually, Prusty has been interacting on Twitter ~1x a week quite consistently even before the fundraiser began.

Badpack said:
He seems to think its a neurohormone thats doing the mitochondrial fission. Read some papers about ß-adrenergic signaling and mitos here. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297546/ So do we end up at autoimmune produced adrenergic stimuli again ?
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I couldn't find a tweet from Prusty saying that the factor he's identified is a neurohormone. Is that something he has alluded to in the past? His presentation at the NIH conference in April 2019 made no mention of that either.

He only tweeted that the factor is not a viral particle but a cellular component.
 
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strategist said:
Can anyone explain what kind of extracellular signals would induce mitochondrial fission?

Also what does it mean that cells are doing a lot of mitochondrial fission, does it occur in response to an impairment in energy production?
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In case it helps
Although mitochondria are commonly depicted as singular oval-shaped structures, it has been known for at least a century that they form a highly dynamic network within most cells where they constantly undergo fission and fusion.[1] Mitochondria can divide by prokaryotic binary fission and since they require mitochondrial DNA for their function, fission is coordinated with DNA replication. Some of the proteins that are involved in mitochondrial fission have been identified and some of them are associated with mitochondrial diseases.[2] Mitochondrial fission has significant implications in stress response and apoptosis.[3]
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https://en.wikipedia.org/wiki/Mitochondrial_fission

So fission isn't necessarily bad.

As an example of that,
Physiological Mitochondrial Fragmentation Is a Normal Cardiac Adaptation to Increased Energy Demand.
RATIONALE:
Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Paradigms have held that mitochondrial fission and fragmentation are the result of pathological stresses, such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in decreased mitochondrial function and cardiac impairment, suggesting that fission is important for maintaining cardiac and mitochondrial bioenergetic homeostasis.

OBJECTIVE:
The purpose of this study is to determine whether mitochondrial fission and fragmentation can be an adaptive mechanism used by the heart to augment mitochondrial and cardiac function during a normal physiological stress, such as exercise.

METHODS AND RESULTS:
We demonstrate a novel role for cardiac mitochondrial fission as a normal adaptation to increased energetic demand. During submaximal exercise, physiological mitochondrial fragmentation results in enhanced, rather than impaired, mitochondrial function and is mediated, in part, by β1-adrenergic receptor signaling. Similar to pathological fragmentation, physiological fragmentation is induced by activation of dynamin-related protein 1; however, unlike pathological fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. Inhibition of fission with P110, Mdivi-1 (mitochondrial division inhibitor), or in mice with cardiac-specific dynamin-related protein 1 ablation significantly decreases exercise capacity.

CONCLUSIONS:
These findings demonstrate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise, as well as providing additional support for the evolving conceptual framework, where mitochondrial fission and fragmentation play a role in the balance between mitochondrial maintenance of normal physiology and response to disease.
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https://www.ncbi.nlm.nih.gov/pubmed/29233845
 
A speculation based on my very limited layman's understanding might be that if we have something in our blood that limits energy production, this might spur the mitochondria to attempt to compensate by splitting (with the 'intention' of increasing the number of functioning mitochondria). However, if the same, or perhaps even an additional, "something in the blood" impairs that process somehow, all we might end up with is fragmented mitochondria that are less efficient - until, perhaps, the something in the blood is cleared or becomes less concentrated.
 
I am very severe, I have been in contact with Dr. Bhupesh, my family has met him. Being a realist, having a little understanding of the complexity of the issue at hand and especially the knowledge that there is so much we do not understand about mitochondria I doubt this will be a breakthrough soon. But what I definitely do not doubt is the sincerity of Dr. Bhupesh and his work to try to get closer to an answer! He has a very refreshing approach to this disease and its patients, we need more of that. We need more crowdfunding for researchers like him, we need to invest more in ourselves and our future, this will only increase the chance of get big money like only NIH is capable of spending. Stop buying that bullshit supplement, give that money to research instead. I am also a big fan of OMF, but they seem to go down the wrong road with their metabolic trap centric funding, also I find them relatively uncreative when it comes to collecting money and informing patients about what they are doing precisely.
 
butter. said:
also I find them relatively uncreative when it comes to collecting money and informing patients about what they are doing precisely.
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what do you mean, i just last week got an email telling me that OMF employed a PhD student with a big DONATE NOW button at the bottom for the big news. Whats next, Fluge and Melle got a new facility manager - DONATE NOW. (sarcasm off)
 
@butter sorry you are so bad. Thank you for telling us a but about Bhupesh. He certainly comes across as sincere to me, good to hear that people who've had 'non-twitter' contact with him think so too.
I think he's made it clear there is no 'quick win' in his tweets, but it's nice to have a little hope.
 
Badpack said:
@cassava7 we contacted him this week.
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Thanks for letting us know :)

Looking at this list of neurohormones, issues with releasing and neurohypophysial hormones can arguably be ruled out. Otherwise blood tests would show them in most people with ME.

This leaves us with two interesting categories:

- adrenomedullary hormones: epinephrine, norepinephrine, dopamine, which are secreted by the adrenal glands. Could be involved in cardiovascular issues in ME, including orthostatic intolerance?
- enteric neurohormones: serotonin and histamine secreted by enterochromaffin cells in the gut.

Given that the microbiome is known to be affected (OMF's Severely Ill Patient Study), that serotonin is a product of tryptophan metabolism (metabolic trap theory) and that food intolerances and MCAS are common comorbidities of ME, this second category sounds relevant.

All neurohormones have a small molecular mass, so would this concur with Ron Davis' point that the factor(s) in the blood is/are not large molecules?

Sorry if there's a lot of nonsensical babble here.
 
@cassava7 i suggest watching this video

its about a guy who had the most severe fatigue and recovered after they surgically removed both adrenal glands. Nothing else worked for him. No medication. Not even the removal of one gland. Both needed to go.
 
Badpack said:
@cassava7 i suggest watching this video

its about a guy who had the most severe fatigue and recovered after they surgically removed both adrenal glands. Nothing else worked for him. No medication. Not even the removal of one gland. Both needed to go.
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I remember reading CNN's piece on his story (https://edition.cnn.com/2019/07/27/health/doug-lindsay-invented-surgery-trnd/index.html). Adrenal dysfunction is a major problem, but is there any previous study or data that would point towards it in ME?
 
@cassava7 nothing clear yet, but if he gets in this state of deep fatigue, and with the studies i have seen, i think the mitochondrial fission is coming from the adrenergic system. Not saying this is important for Cfs. The mitochondrial fission seen in Cfs could be just a side effect and not really important for the systems in the end. But im just guessing here like everyone else.
 
strategist said:
Can anyone explain what kind of extracellular signals would induce mitochondrial fission?
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Increase in Dynamin-1-like protein (which is involved in fission) and inhibition of the proteins that lead to fusion, namely mitofusion 1 and 2.
https://en.wikipedia.org/wiki/DNM1L
https://en.wikipedia.org/wiki/MFN1
https://en.wikipedia.org/wiki/MFN2 (which are quite similar to a yeast enzyme involved in yeast budding)

Also what does it mean that cells are doing a lot of mitochondrial fission, does it occur in response to an impairment in energy production?
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Increased energetic demand. The separated mitochondria have increased surface area which can increase their energetic output, though increases their vulnerability to damage by reactive oxygen species and the like.

I suspect it is a positive adaptation, rather than a perpetuating factor.


Eduardo Silva Ramos said:
The fact that mitochondrial bioenergetics status cannot be systematically linked to specific mitochondrial morphologies show that the mitochondrial network morphology is a poor marker of OXPHOS activity. However, beyond mitochondrial network morphology, mitochondrial bioenergetics and OPA1-mediated IMM fusion are reportedly linked.
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https://www.sciencedirect.com/science/article/pii/S0005272816300858
They go on to state that MFN2 activity is important "in regulating the mevalonate biosynthesis pathway, which, in turn, is required to maintain mitochondrial coenzyme Q levels".

Notably CoQ10 levels are lower during viral infection and lower CoQ10 levels lead to greater resistance to viruses (but may increase susceptibility to bacterial infection)...
 
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Badpack said:
@cassava7 i suggest watching this video

its about a guy who had the most severe fatigue and recovered after they surgically removed both adrenal glands. Nothing else worked for him. No medication. Not even the removal of one gland. Both needed to go.
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I assume that there was some indication of a problem with the functioning of the adrenal system - levels of hormones excreted or increased sensitivity to the hormone.

Jonas Bergquist found Pregnenolone to be significantly lower in people with ME [OMF funded study - https://let-me.be/e107_files/downloads/the_me_global_chronicle_-_30_-_20181222.pdf].
 
If the coming paper from Dr. Prusty has profound and lasting mitochondrial news, we need to get SS31/Elamipretide to patients to try it out as fast as possible imo. I have high hopes here because its stops mitochondrial fission. Im looking for it for ages now but besides shady china alibaba deals its waiting for an FDA approved med.
 
strategist said:
Can anyone explain what kind of extracellular signals would induce mitochondrial fission?
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Is it extracellular? In one of his tweets, when asked if the factor is a viral particle, Prusty says "No, it's a cellular component."

That sounds more like Dynamin-related protein 1 (Drp1). [As mentioned by @Snow Leopard above.]


I don't know if it's relevant, but I found this paper on mitochondrial fission and fusion which suggests that fission can be used to dispose of a badly damaged part of a mitochondrion, while fusion may be employed to "rescue" a more viable mitochondrion by combining it with a healthier one - the result being a larger but somewhat less healthy mitochondrion.

It may be erroneous to think of mitochondrial fission in terms of a dividing cell that produces two identical copies. At least some of the time, fission may just be a way of getting rid of a part of a mitochondrion that might otherwise spread damage to the rest of it.
 
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Facebook post from @Simon M
Hot from the lab: Dr Bhupesh Prusty tweeted early results showing that a factor isolated from the blood of #mecfs patients causes mitochondria, the powerplants of the cell, to behave abnormally in healthy cells.*These findings have not yet been peer-reviewed or published*. If these findings prove good enough to be published and are replicated, they would be very important indeed. Mitochondria turn food molecules into packets of energy that power almost all the processes of the body, from digestions and the immune system to moving about and nerve impulses. They also play an important role in the immune system, including helping fight off viruses.
The photo shows a healthy cell on the left and its nucleus is blue. The fluorescent green picks out mitochondria that are fusing together. It turns out that normal, healthy mitochondria are constantly fusing together and splitting apart again (I know, it sounds weird). On the right is a healthy cell that has been incubated for 24 hours with a factor extracted from the blood serum of ME/CFS patients. Note there is much less green, indicating the mitochondrial are now not fusing together as they should.

https://twitter.com/BhupeshPrus…/status/1233508017368436737…

Showing that there is a molecule (or molecules) in the blood of ME/CFS patients that causes mitochondria to behave abnormally would be a big step forward in ME/CFS research

Bhupesh Prusty says they have isolated a molecule from blood serum that has this effect and it is a normal component of the cell (though he doesn't say what the molecule a is). He adds that there will be other molecules/factors in the blood of ME/CFS patients.

Prusty is at the University of Wurzburg in Germany.
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Code: 
https://www.facebook.com/topmecfsresearch/posts/907217086399909


Do we know the results of a healthy cell in control serum incubated for 24 hours? Is it still different to the healthy cell incubated with 'extract of patient'?
 
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