Mitochondrial impairment but not peripheral inflammation predicts greater Gulf War illness severity, 2023, Patel et al

rvallee

rvallee

Senior Member (Voting Rights)
Mitochondrial impairment but not peripheral inflammation predicts greater Gulf War illness severity
https://www.nature.com/articles/s41598-023-35896-w
Published: 12 July 2023


Gulf War illness (GWI) is an important exemplar of environmentally-triggered chronic multisymptom illness, and a potential model for accelerated aging. Inflammation is the main hypothesized mechanism for GWI, with mitochondrial impairment also proposed. No study has directly assessed mitochondrial respiratory chain function (MRCF) on muscle biopsy in veterans with GWI (VGWI).

We recruited 42 participants, half VGWI, with biopsy material successfully secured in 36. Impaired MRCF indexed by complex I and II oxidative phosphorylation with glucose as a fuel source (CI&CIIOXPHOS) related significantly or borderline significantly in the predicted direction to 17 of 20 symptoms in the combined sample.

Lower CI&CIIOXPHOS significantly predicted GWI severity in the combined sample and in VGWI separately, with or without adjustment for hsCRP. Higher-hsCRP (peripheral inflammation) related strongly to lower-MRCF (particularly fatty acid oxidation (FAO) indices) in VGWI, but not in controls. Despite this, whereas greater MRCF-impairment predicted greater GWI symptoms and severity, greater inflammation did not.

Surprisingly, adjusted for MRCF, higher hsCRP significantly predicted lesser symptom severity in VGWI selectively. Findings comport with a hypothesis in which the increased inflammation observed in GWI is driven by FAO-defect-induced mitochondrial apoptosis. In conclusion, impaired mitochondrial function—but not peripheral inflammation—predicts greater GWI symptoms and severity.
 
Mitochondrial complex 1- a wee bit familiar sounding .
No compensatory complex 5 uprating ?.
rvallee said:
Mitochondrial impairment but not peripheral inflammation predicts greater Gulf War illness severity
https://www.nature.com/articles/s41598-023-35896-w
Published: 12 July 2023


Gulf War illness (GWI) is an important exemplar of environmentally-triggered chronic multisymptom illness, and a potential model for accelerated aging. Inflammation is the main hypothesized mechanism for GWI, with mitochondrial impairment also proposed. No study has directly assessed mitochondrial respiratory chain function (MRCF) on muscle biopsy in veterans with GWI (VGWI).

We recruited 42 participants, half VGWI, with biopsy material successfully secured in 36. Impaired MRCF indexed by complex I and II oxidative phosphorylation with glucose as a fuel source (CI&CIIOXPHOS) related significantly or borderline significantly in the predicted direction to 17 of 20 symptoms in the combined sample.

Lower CI&CIIOXPHOS significantly predicted GWI severity in the combined sample and in VGWI separately, with or without adjustment for hsCRP. Higher-hsCRP (peripheral inflammation) related strongly to lower-MRCF (particularly fatty acid oxidation (FAO) indices) in VGWI, but not in controls. Despite this, whereas greater MRCF-impairment predicted greater GWI symptoms and severity, greater inflammation did not.

Surprisingly, adjusted for MRCF, higher hsCRP significantly predicted lesser symptom severity in VGWI selectively. Findings comport with a hypothesis in which the increased inflammation observed in GWI is driven by FAO-defect-induced mitochondrial apoptosis. In conclusion, impaired mitochondrial function—but not peripheral inflammation—predicts greater GWI symptoms and severity.
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I can't believe people with GWI have suffered for so long (30+years) with so little research. I know pwME have done the same, but I've only been ill 5 years and entered the ME world in 2021, when LC was well-known and the new NICE guidelines came out.
 
Although stress had been emphasized early on as a hypothesized cause of GWI24,25, the ground war lasted only 4 days26 and many of those deployed never saw combat. Combat stress is not an independent predictor in regressions that adjust for other exposures26. In contrast, chemical exposures such as acetylcholinesterase inhibitor exposures have been documented to play a role20. Evidence for a causal role includes dose–response information20, as well as gene-environment interaction support27.
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Acetylcholinesterase inhibitors might be the common factor in illnesses like GWI, including in ME/CFS and chronic ciguatera.

Mitochondrial impairment, long proposed33, has more recently had the benefit of supporting data9,34,35,36,37,38,39, including objective evidence of impaired bioenergetic function34,35 and favorable response to treatment with coenzyme Q10 (a mitochondrial coenzyme) relative to placebo. Coenzyme Q10 significantly alleviated GWI symptoms and improved objectively measured physical function, in a double-blind randomized controlled trial9.
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Ref #9
Golomb, B. A. et al. Coenzyme Q10 benefits symptoms in Gulf War veterans: Results of a randomized double-blind study. Neural Comput.26, 2594–2651. https://doi.org/10.1162/NECO_a_00659 (2014).
I'll be surprised if this report of CoQ10 helping GWI checks out, but maybe it will. I'll make a thread.

Edit:
Thread here: Coenzyme Q10 Benefits Symptoms in Gulf War Veterans: Results of a Randomized Double-Blind Study, 2014, Golomb et al
No significant benefit for primary outcome (self-rated general health) for both the 100mg and 300mg CoQ10 treatment arms.
 
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Nobody should be surprised about this. It will be a similar picture in ME/CFS, despite what has been said (on this forum) about (secondary) mitochondrial diseases and how they differ from what we call ME/CFS.
 
Cells from a muscle biopsy: 19 GWI; 17 controls
14 matched pairs for a subset analysis
There was some missing data - actual numbers contributing to reported means isn't reported.

There were 19 different assessments made of mitochondrial function (results in Supplementary Table 1); hsCRP was also assessed.
5 measures are reported in Table 2.
None were anywhere near significant in the total sample. Two (listed below) were only just significant in the paired analysis (p=0.05 and p=0.04)

I think there has to be a fair amount of doubt about the importance of these findings, due to the number of assessments made, the relatively small number of participants and the low level of significance.

CI&CII&FAOCI/CIIOXPHOS
Determined by using fatty acids as the fuel source with complex I and II substrates malate, glutamate, pyruvate, and succinate with ADP to drive respiration
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Paired analysis: P=0.039. Means(SD) GWI=46 (24); HC=72 (30)
Whole analysis: P=0.23. Means(SD) GWI=51 (24); HC = 63 (30)
Substantial standard deviations

FAOMaxUC
Determined by using fatty acids as the fuel source with FCCP as an uncoupler
Paired analysis: P=0.049. Means(SD) GWI=68 (27); HC=102 (46)
Whole analysis: P=0.20. Means(SD) GWI=75(30); HC = 92 (42)
Substantial standard deviations

There might be something in here, but the study needs to be repeated with a substantially larger sample, so that there is the potential to identify participant subsets. Possibly the findings are a result of lower activity levels (and therefore lower regular demands on energy production) in the GWI participants.

Interestingly, they found a good negative relationship between CI&CII&FAOCI/CIIOXPHOS and 'post-exertional fatigue' (p=0.014). hsCRP was not associated with post-exertional fatigue but was with 'tiredness'.

They conclude, on the basis of the lack of a difference in hsCRP that inflammation pays no role in GWI. This may be true, but I think we have seen recently that there can still be elements of inflammation without elevated hsCRP. (I've deleted this point as I'm not sure now what the paper claims about inflammation; it might say both it might and might not be important. I don't have the energy to go back and check.)
 
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butter. said:
Nobody should be surprised about this. It will be a similar picture in ME/CFS, despite what has been said (on this forum) about (secondary) mitochondrial diseases and how they differ from what we call ME/CFS.
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Definitely. I predict we'll discover their pathology is very similar, if we can unravel GWI before most of their cohort passes away and can't be studied anymore.
 
RedFox said:
Definitely. I predict we'll discover their pathology is very similar, if we can unravel GWI before most of their cohort passes away and can't be studied anymore.
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Or the next cohort comes along. Guaranteed. Probably not identical, but issues like this are sadly common, and they are very rarely studied at all.
 
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