An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients Missailidis et al. 2019

https://www.preprints.org/manuscript/201909.0043/v1

 

So according to this, the cells are still able to operate thanks to compensatory changes but they don't handle additional energy demands well. That sounds similar to ME/CFS.

 

Sigh

 

This is really exciting on first skim. There are lots of test results with big separation between controls and patients (CCC qualified), with low p numbers. Lots of hard data.
Paper was originally presented in this talk
https://www.s4me.info/threads/video...nsatory-changes-in-me-cfs-patient-cells.9177/

And follow-up study planned
https://www.s4me.info/threads/austr...ded-for-study-in-melbourne.11113/#post-198497

Would be fantastic if we could persuade Karl Morten to run a parallel study in real time with Paul Fisher on a spearate cohort and different lab to speed up validation of this work.

I think this is the first time we have seen such detailed differences in the analysis of mitochondria patient vs control!

 

Paul Fisher is quoted in the press release for the Australian Biobank to be funded by the Mason foundation.
https://www.eqt.com.au/about-us/med...ld-decision-to-back-a-plan-for-a-breakthrough

Could this paper possibly describe the meat and potatoes of a diagnostic test. See section 3.7 "Stress-sensing pathways in ME/CFS are perturbed – TORC1 is chronically hyperactivated"

These p numbers and difference between patients and controls for this test have me rather excited.

 

@wigglethemouse I also find the increase in carnitine pathway interesting. I think carnitine helps me.

 

Fwiw, I am a responder to Rapamune / Rapamycin, an mTOR inhibitor.

(ETA format)

 

Does the paper address how this impairment in Complex V could happen in enough mitochondria / cells simultaneously to account for the "sudden" onset often seen in the illness? It seems like some sort of exposure to a system wide "trigger" would be needed (or some kind of signaling in response to a "trigger").

 

So what this study tells is that healthy controls are more active.

It is one thing to criticize patient/control selection as a semantical issue (to make results generalizable), but is another to criticize the control selection and knowing why the underlying physiology could nullify it.

 

The only thing that helps me is fasting for 1-3 days. Coincidentally fasting also reduces mTOR activity.

 

Yeah, when I am at my very sickest experiencing a PEM that makes me so weak, with retching as if I were poisoned, I cannot bear to eat, even though my stomach is rumbling with hunger I just can't eat at the mouth. I have to nibble every 15 minutes and sip on some liquid. It's a strange thing to be hungry at the stomach but no appetite at the mouth - to eat and to swallow is very difficult.

I dread this severe PEM because I fear I am not going to come out of this kind of PEM and will be left very weak and unable to look after myself. Thankfully I always do improve out of it. But this kind of PEM starves me as if the ME/PEM itself is putting me through a fasting - maybe this is the body just trying to help me out of this severe state by resting completely.

 

Im waiting for the layman version, but was wondering if this could be relevant to the slightly elevated risk of non hodgkins lymphoma for ME-patients?

 

I always feel like my life is going great when I`m lying on my back after making dinner, picking potatoes from the plate with my hand, cus I`m completely devoid of human function

Very few sees just how nightmarish ME can be, and only us feel it too.

Luckily I`m too exhausted to self-pity

 

A signalling problem then.

 

From "something in the blood" ?

 

I sent a message to the authors politely suggesting a more accurate way to phrase this - and I had a reply to the effect that they use the word fatigue because it's used in the CCC but that they will look at rephrasing the 'unaided by rest' bit. It may or may not be too late for this particular paper but they'll keep it in mind for future publications. A big thumbs up to responsive researchers

Oh, and I also thanked them for their interesting work

 

I think this is the puzzle with results like this.

If a difference survives through to immortalised lymphoblasts in culture it seems unlikely to have anything to do with some systemic signal that arises when the illness arises. That leaves a purely genetic difference as an explanation but then it is hard to understand why people are normal before the illness starts.

It may be that we have to assume that some irreversible signal affected the differentiation of these cells and this is carried over in immortalised cells. This would be unexpected since immortalisation tends to override such differentiation signals.

Another possibility is that it is all due to which subtypes of cells are sampled. If more of the cells in ME blood are lymphocytes of a subgroup p rather than a subgroup q then when cells are immortalised they may appear to behave differently. In that situation we would not be able to draw any conclusions from the difference in culture about what disease mechanism is. The difference in culture wold not be due to cells behaving a different way, just a different proportion of cells behaving a particular way.

This comes back to my main worry about all these studies. Lymphocytes in the blood are not doing anything important there. They are just resting cells moving from A to B for one reason or another. Their function is of no real interest. People with different levels of activity or diet may have different proportions of cells in the blood of different types for reasons nothing to do with the illness.