Mitochondra in ME/CFS

[percyval577]

According to some recent findings and articles it appears to be unlikely that an intrinsic mt problem is the problem in ME/CFS. Therefore, any possible problems may be caused upstream.

___________​

Mitochondrial DNA variants correlate with symptoms in [ME/CFS]
Billig-Ross et al 2016


abstract

BACKGROUND:
Mitochondrial dysfunction has been hypothesized to occur in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a disease characterized by fatigue, cognitive difficulties, pain, malaise, and exercise intolerance. We investigated whether haplogroup, single nucleotide polymorphisms (SNPs), or heteroplasmy of mitochondrial DNA (mtDNA) were associated with health status and/or symptoms.

METHODS:
Illumina sequencing of PCR-amplified mtDNA was performed to analyze sequence and extent of heteroplasmy of mtDNAs of 193 cases and 196 age- and gender-matched controls from DNA samples collected by the Chronic Fatigue Initiative. Association testing was carried out to examine possible correlations of mitochondrial sequences with case/control status and symptom constellation and severity as reported by subjects on Short Form-36 and DePaul Symptom Questionnaires.

RESULTS:
No ME/CFS subject exhibited known disease-causing mtDNA mutations. Extent of heteroplasmy was low in all subjects. Although no association between mtDNA SNPs and ME/CFS vs. healthy status was observed, haplogroups J, U and H as well as eight SNPs in ME/CFS cases were significantly associated with individual symptoms, symptom clusters, or symptom severity.

CONCLUSIONS:
Analysis of mitochondrial genomes in ME/CFS cases indicates that individuals of a certain haplogroup or carrying specific SNPs are more likely to exhibit certain neurological, inflammatory, and/or gastrointestinal symptoms. No increase in susceptibility to ME/CFS of individuals carrying particular mitochondrial genomes or SNPs was observed.

open access
J Transl Med. 2016 Jan 20;14:19. doi: 10.1186/s12967-016-0771-6. ​

 

[percyval577]

Clinically proven mtDNA mutations are not common in those with [CFS]
Schoeman et al 2017

BACKGROUND:
Chronic Fatigue Syndrome (CFS) is a prevalent debilitating condition that affects approximately 250,000 people in the UK. There is growing interest in the role of mitochondrial function and mitochondrial DNA (mtDNA) variation in CFS. It is now known that fatigue is common and often severe in patients with mitochondrial disease irrespective of their age, gender or mtDNA genotype. More recently, it has been suggested that some CFS patients harbour clinically proven mtDNA mutations.

METHODS:
MtDNA sequencing of 93 CFS patients from the United Kingdom (UK) and South Africa (RSA) was performed using an Ion Torrent Personal Genome Machine. The sequence data was examined for any evidence of clinically proven mutations, currently; more than 200 clinically proven mtDNA mutations point mutations have been identified.

RESULTS:
We report the complete mtDNA sequence of 93 CFS patients from the UK and RSA, without finding evidence of clinically proven mtDNA mutations. This finding demonstrates that clinically proven mtDNA mutations are not a common element in the aetiology of disease in CFS patients. That is patients having a clinically proven mtDNA mutation and subsequently being misdiagnosed with CFS are likely to be rare.

CONCLUSION:
The work supports the assertion that CFS should not be considered to fall within the spectrum of mtDNA disease. However, the current study cannot exclude a role for nuclear genes with a mitochondrial function, nor a role of mtDNA population variants in susceptibility to disease. This study highlights the need for more to be done to understand the pathophysiology of CFS.

open access
BMC Med Genet. 2017 Mar 16;18(1):29. doi: 10.1186/s12881-017-0387-6.​

 

[percyval577]

Perceived fatique is highly prevalent and debilitataing in patients with mitochondrial disease
Gorman et al 2014


from the abstract

Perceived fatigue is a prominent symptom in patients with mitochondrial disease but to date its prevalence, impact and aetiology are poorly understood. ... (response rate: 60%; n = 132). ... using the Fatique Imapct Scale. ... Other putative biological mechanisms were evaluated using the Hospital Anxiety Depression scale and Epworth sleepiness scale. Data were compared with those for healthy control subjects and patients with Myalgic Encephalopathy/Chronic Fatigue Syndrome matched for age and gender. Sixty-two per cent of patients with mitochondrial disease reported excessive symptomatic fatigue (Fatigue Impact Scale ≥ 40); whilst 32% reported severe, functionally limiting fatigue symptoms (Fatigue Impact Scale ≥ 80) comparable to perceived fatigue in patients with Myalgic Encephalopathy/Chronic Fatigue Syndrome. Fatigue is common and often severe in patients with mitochondrial disease irrespective of age, gender or genotype. Future evaluation of causal factors in mitochondrial disease-associated fatigue is warranted with the potential to guide future treatment modalities.

open access
Neuromuscul Disord. 2015 Jul;25(7):563-6. doi: 10.1016/j.nmd.2015.03.001. Epub 2015 Apr 23.​

Figure 1

 

[percyval577]

MtDNA population variation in [ME/CFS] in two populations: a study of mildly deleterious variants
Venter et al 2019


abstract

Myalgic Encephalomyelitis (ME), also known as Chronic Fatigue Syndrome (CFS) is a debilitating condition. There is growing interest in a possible etiologic or pathogenic role of mitochondrial dysfunction and mitochondrial DNA (mtDNA) variation in ME/CFS. Supporting such a link, fatigue is common and often severe in patients with mitochondrial disease. We investigate the role of mtDNA variation in ME/CFS. No proven pathogenic mtDNA mutations were found. We then investigated population variation. Two cohorts were analysed, one from the UK (n = 89 moderately affected; 29 severely affected) and the other from South Africa (n = 143 moderately affected). For both cohorts, ME/CFS patients had an excess of individuals without a mildly deleterious population variant. The differences in population variation might reflect a mechanism important to the pathophysiology of ME/CFS.

open access
Scientific Reports volume 9, Article number: 2914 (2019) Cite this article​

 

[percyval577]

Mitochondrial complex activity in permealised cells of [CFS] patients using two cell types
Tomas et al 2019


abstract

Abnormalities in mitochondrial function have previously been shown in chronic fatigue syndrome (CFS) patients, implying that mitochondrial dysfunction may contribute to the pathogenesis of disease. This study builds on previous work showing that mitochondrial respiratory parameters are impaired in whole cells from CFS patients by investigating the activity of individual mitochondrial respiratory chain complexes. Two different cell types were used in these studies in order to assess individual complex activity locally in the skeletal muscle (myotubes) (n = 6) and systemically (peripheral blood mononuclear cells (PBMCs)) (control n = 6; CFS n = 13). Complex I, II and IV activity and respiratory activitysupported by fatty acid oxidation and glutaminolysis were measured usingextracellular flux analysis. Cells were permeabilised and combinations of substrates and inhibitors were added throughout the assays to allow states of mitochondrial respiration to be calculated and the activity of specific aspects of respiratory activity to be measured. Results showed there to be no significant differences in individual mitochondrial complex activity or respiratory activity supported by fatty acid oxidation or glutaminolysis between healthy control and CFS cohorts in either skeletal muscle (p ≥ 0.190) or PBMCs (p ≥ 0.065). This is the first study to use extracellular flux analysisto investigate individual mitochondrial complex activity in permeabilised cells in the context of CFS. The lack of difference in complex activity in CFS PBMCs suggests that the previously observed mitochondrial dysfunction in whole PBMCs is due to causes upstream of the mitochondrial respiratory chain.

open access
PeerJ. 2019; 7: e6500. Published online 2019 Mar 1. doi: 10.7717/peerj.6500​

 

[MTpockets]

Thanks for sharing this.

 

[Wishful]

My question to them would be: Did you check cerebral mtDNA? My experience is that ME involves cerebral cells, and it's possible that there's a mutation (or epigenetic factor?) involving the differences between the two types of DNA.

BTW, researchers sure don't make it easy to contact them via email. I'd send them that question if I could figure out how.

 

[Rufous McKinney]

it appears to be unlikely that an intrinsic mt problem is the problem in ME/CFS. Therefore, any possible problems may be caused upstream

These studies are mostly focused on- having a genetic mitochondrial disease.

We likely do NOT have a genetic mitochondrial disease. So this is NOT saying- our mitochrondria are fine.

 

[Wishful]

I wondered about the limitations of what they considered genetic mitochondrial disease. It doesn't need to be something with obvious symptoms itself; it just needs to bias some function which then leads to ME. A better search might be correlations of each gene in ME victims vs controls. Even that's not guaranteed to find anything, because it might be a problem of gene activation. A gene might be there to be detected, but maybe its rate of producing RNA is incorrect.

 

[SlamDancin]

Would hypoxia be above the ETC?

 

[Rufous McKinney]

I wondered about the limitations of what they considered genetic mitochondrial disease.

thinking about episode One of Diagnosis, that young woman ended up getting diagnosed in Italy, by pediatricians who understand genetic mitochondrial diseases. That was interesting. I suspect ours are ok, but then something is later going wrong.

 

[percyval577]

Would hypoxia be above the ETC?

I have forgotten the details for now, but it is induced by certain factors, so not rather an intrinsic mt thing (I remember slightly Nitric Oxide and Hypoxid-Inducing-Factor = HIF one and two, I think).

But it also can be induced, at lest to a certain degree, when the ETC struggles a bit (probably an event normal enough). Again, I have forgotten all details for now, hope it is right.

 

[percyval577]

I wondered about the limitations of what they considered genetic mitochondrial disease. It doesn't need to be something with obvious symptoms itself; it just needs to bias some function which then leads to ME.

Here Billig-Ross et al say that they didn´t observe any predisposition, whereas Schoeman et al don´t want to exclude this possibility.

A better search might be correlations of each gene in ME victims vs controls. Even that's not guaranteed to find anything, because it might be a problem of gene activation. A gene might be there to be detected, but maybe its rate of producing RNA is incorrect.

I think a problem with activation is not ruled out by any of the studies, but they would say that it isn´t a problem in the mitochondria, especially Tomas et al 2019 are saying this.

My question to them would be: Did you check cerebral mtDNA? My experience is that ME involves cerebral cells, and it's possible that there's a mutation (or epigenetic factor?) involving the differences between the two types of DNA.

I too think that a malfunctioning brain is core in ME/CFS. I think epigenetic factors are ruled out in the lines they looked at (Tomas et al mention the two ones they looked at), and I think you are right that in the brain epigentic changes might have been implanted.

Though what strikes me, is that Venter et al found that the mitochindria in ME/CFS even are in a better shape than that of healthy controls. This strongly suggest that it is a compensatory mechanism to some hindering effect upstream.

 

[Wishful]

This strongly suggest that it is a compensatory mechanism to some hindering effect upstream.

Another possibility is an alteration to signals downstream. A normal level of something could provide an incorrect feedback signal. Any part of a feedback loop can cause an abnormal output.

 

[percyval577]

Any part of a feedback loop can cause an abnormal output.

I for sure don´t want to deny this.

Another possibility might be that there is happening very good maintenance or so [without being part of a compensation], in accordance with Billig-Roiss et al who found hetero-plasmy to be low (the mt DNA is cared also for, what was thought not to happen only some years ago). Or the mitochindria haven´t been used much, and not much mutation has accumulated, more unlikely though, I think.


edit:
[Maybe a maintenance or so (making new cells) of the nuclear DNA in ME/CFS could be seen here: Rajeevan 2018]

 

[Frunobulax]

These studies are mostly focused on- having a genetic mitochondrial disease.

We likely do NOT have a genetic mitochondrial disease. So this is NOT saying- our mitochrondria are fine.

Exactly. A genetic issue should manifest itself in early life, but many ME patients were pretty active (exercise, physical activity) before ME onset. I always describe it as a kind of a metabolic switch that we haven't found, suddenly we don't function anymore. If there is a genetic issue then it's epigenetic and not on DNA level. And I would expect it to be related to the immune system (causing immunodeficiency), otherwise we wouldn't have frequent onset with a viral infection.

Now if we could just find that wretched switch

To me the jury is still out whether ME runs in families, beyond environmental influences. A family shares housing, food and environmental toxins. The question is if a relative of a ME patient living 1000 miles or more away is more likely to get ME. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128000/ indicates that this may be the case, but they didn't try to control the environmental factors. After all, a cousin is more likely to live nearby than far away, isn't it?

Can anyone recommend a good introduction to epigenetics?

 

[Wishful]

Now if we could just find that wretched switch

What makes it even more irritating is that I managed to flip that switch eight or so times (but it kept flipping back on its own). I even managed to identify some of the ways to flip it (prednisone, cumin, T2). However, that hasn't helped to locate the switch. We're still just poking in the dark...

 

[beatsmyth]

I even managed to identify some of the ways to flip it (prednisone, cumin, T2).

which switches do all these have in common. If we an figure that out then we have something to go on

 

[Frunobulax]

What makes it even more irritating is that I managed to flip that switch eight or so times (but it kept flipping back on its own). I even managed to identify some of the ways to flip it (prednisone, cumin, T2).

Theory: Could be that we have immunodeficiency and a viral/bacterial infection. If we help our immune system to defeat them we'll be fine - until the next virus or bacterial infection comes around. However, we really need to fix the immunodeficiency.

 

[Wishful]

I don't feel that my ME is viral related. Viral infections do make my symptoms worse, but then it goes back to baseline. I think I've only noticed two viral infections since 2001.

which switches do all these have in common. If we an figure that out then we have something to go on

Prednisone affects the immune system...and also does many other things. T2 (3-5 diiodothyronine) takes part in RNA transcription...and does many other things. Cuminaldehyde...no idea.