A possible role for mitochondrial-derived peptides humanin and MOTS-c in patients with Q fever fatigue syndrome and CFS, 2019, Raijmakers et al

[Andy]

Background
Q fever fatigue syndrome (QFS) is a well-documented state of prolonged fatigue following around 20% of acute Q fever infections. It has been hypothesized that low grade inflammation plays a role in its aetiology. In this study, we aimed to identify transcriptome profiles that could aid to better understand the pathophysiology of QFS.

Methods
RNA of monocytes was collected from QFS patients (n = 10), chronic fatigue syndrome patients (CFS, n = 10), Q fever seropositive controls (n = 10), and healthy controls (n = 10) who were age- (± 5 years) and sex-matched. Transcriptome analysis was performed using RNA sequencing.

Results
Mitochondrial-derived peptide (MDP)-coding genes MT-RNR2 (humanin) and MT-RNR1 (MOTS-c) were differentially expressed when comparing QFS (− 4.8 log2-fold-change P = 2.19 × 10−9 and − 4.9 log2-fold-change P = 4.69 × 10−8), CFS (− 5.2 log2-fold-change, P = 3.49 × 10−11 − 4.4 log2-fold-change, P = 2.71 × 10−9), and Q fever seropositive control (− 3.7 log2-fold-change P = 1.78 × 10−6 and − 3.2 log2-fold-change P = 1.12 × 10−5) groups with healthy controls, resulting in a decreased median production of humanin in QFS patients (371 pg/mL; Interquartile range, IQR, 325–384), CFS patients (364 pg/mL; IQR 316–387), and asymptomatic Q fever seropositive controls (354 pg/mL; 292–393).

Conclusions
Expression of MDP-coding genes MT-RNR1 (MOTS-c) and MT-RNR2 (humanin) is decreased in CFS, QFS, and, to a lesser extent, in Q fever seropositive controls, resulting in a decreased production of humanin. These novel peptides might indeed be important in the pathophysiology of both QFS and CFS.

Open access, https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-1906-3

 

[Andy]

Research[edit]
Experiments using cultured cells have demonstrated that humanin has both neuroprotective as well as cytoprotective effects and experiments in rodents have found that it has protective effects in Alzheimer's disease models, Huntington's disease models and stroke models.[13]

Humanin is proposed to have myriad neuroprotective and cytoprotective effects. Both studies in cells and rodents have both found that administration of humanin or humanin derivatives increases survival and/or physiological parameters in Alzheimer's diseasemodels.[14][15] In addition to Alzheimer's disease, humanin has other neuroprotective effects against models of Huntington's disease, prion disease, and stroke.[16][17][18] Beyond the possible neuroprotective effects, humanin protects against oxidative stress, atherosclerotic plaque formation, and heart attack.[19][20][21][22] Metabolic effects have also been demonstrated and humanin helps improve survival of pancreatic beta-cells, which may help with type 1 diabetes,[23] and increases insulin sensitivity, which may help with type 2 diabetes.[24] In rats, the humanin analog appears to normalize glucose levels and reduce diabetes symptoms.[25]

Rattin shows the same ability as humanin to defend neurons from the toxicity of beta-amyloid, the cause of degeneration in Alzheimer's Disease.[6]

Small humanin-like peptides are a group of peptides found in the mitochondrial 16S rRNA, and also possess retrograde signaling functions.

Wikipedia, https://en.wikipedia.org/wiki/Humanin

There are a number of papers out there on MOTS-c, this is just one selected semi-randomly.

Abstract
Mitochondria are ancient organelles that are thought to have emerged from once free-living α-proto-bacteria. As such, they still possess several bacterial-like qualities, including a semi-autonomous genetic system, complete with an independent genome and a unique genetic code. The bacterial-like circular mitochondrial DNA (mtDNA) has been described to encode 37 genes, including 22 tRNAs, 2 rRNAs, and 13 mRNAs. Two additional peptides reported to originate from the mtDNA, namely humanin (Hashimoto et al., 2001; Ikone et al., 2003; Guo et al., 2003) [1-3] and MOTS-c (mitochondrial ORF of the twelve S c) (Lee et al., 2015) [4], indicate a larger mitochondrial genetic repertoire (Shokolenko and Alexeyev, 2015) [5].

These mitochondrial-derived peptides (MDPs) have profound and distinct biological activities and provide a paradigm-shifting concept of active mitochondrial-encoded signals that act at the cellular and organismal level (i.e. mitochondrial hormone) (da Cunha et al., 2015; Quiros et al., 2016) [6,7]. Considering that mitochondria are the single most important metabolic organelle, it is not surprising that these MDPs have metabolic actions. MOTS-c has been shown to target the skeletal muscle and enhance glucose metabolism. As such, MOTS-c has implications in the regulation of obesity, diabetes, exercise, and longevity, representing an entirely novel mitochondrial signaling mechanism to regulate metabolism within and between cells.

https://www.ncbi.nlm.nih.gov/pubmed/27216708

 

[Grigor]

Note that van der Meer is a good friend of Peter White and a CBT promoter.

 

[Hutan]

I posted about Raijmakers' talk at the recent Emerge conference here (post#39), mostly about the part of the talk that was about CBT.

It's interesting that QFS warrants its own name, whereas syndromes arising after various other illnesses seem to get lumped into CFS. At the conference, Raijmakers seemed quite confident that QFS and CFS are different illnesses but I don't think there's much evidence for that. If this team's mitochondrial peptides are relevant, it doesn't look as though QFS and CFS are different. I wonder whether it might just be that these researchers have a stereotype of the CFS sufferer, and she doesn't look much like most of the farmers and meat processors that get Q fever and go on to develop QFS.

The questions at the end are worth a listen too. There was an Australian (a doctor?) who, when the question of whether CFS and QFS are the same came up noted that it's definitely a different disease. 'The people who get QFS are hardworking farmers, nothing like the sort of people who get classic CFS...'

Also in the question time was the mention of an Adelaide professor, Marmion?, now deceased. He seemed to have been well regarded. He apparently found evidence of the Q fever bacteria (perhaps whole bacteria, perhaps polysaccharide debris) in the bone marrow of QFS patients and hypothesised that this was the cause of the ongoing symptoms.

I thought the comment at the conference about the bacteria that causes Q fever being found in bone marrow was interesting, especially given a number of researchers at the conference mentioned bone marrow in passing. It seems that it is quite accepted that the bacteria can lie latent in a person, with the infection resurfacing some years later.

Q fever is an infection caused by the bacterium Coxiella burnetii. Q fever is usually a mild disease with flu-like symptoms. Many people have no symptoms at all. In a small percentage of people, the infection can resurface years later. This more deadly form of Q fever can damage your heart, liver, brain and lungs.

 

[Hutan]

In accordance with this, the first randomized placebo-controlled trial for QFS treatment was recently published, comparing cognitive behavioural therapy (CBT) and doxycycline with placebo treatment, demonstrating a beneficial effect for CBT, but not doxycycline, in reducing fatigue severity at end of treatment

I should be asleep, but ffs. There was a small benefit on a subjective outcome at the end of the trial which completely disappeared at followup.

Chronic fatigue syndrome (CFS) is a disease with a striking overlap in symptoms with QFS that shows a subtle difference in psychological perpetuating factors and inflammatory profile

more swearing from me...

 

[Hutan]

From the abstract:

resulting in a decreased median production of humanin
in QFS patients (371 pg/mL; Interquartile range, IQR, 325–384),
CFS patients (364 pg/mL; IQR 316–387),
and asymptomatic Q fever seropositive controls (354 pg/mL; 292–393).

No figure for humanin in the healthy controls is given in the abstract, and I mistakenly interpreted those figures as decreases in humanin production relative to the healthy controls. Actually they are absolute values. Here's the control result from the Results section:

healthy controls (395 pg/mL; 372–409)

So, actually the data can be lined up with increasing humanin levels:
asymptomatic Q fever seropositive controls = 354 (292-393)
CFS patients = 364 (316-387)
QFS patients = 371 (325-384)
healthy controls = 395 (372-409)

Hmm. Here's the chart.


With only 10 people in each cohort, that's not a convincing result. And, for the other peptide MOTS-c, there was no difference between the 4 cohorts.


So maybe the major finding from this study is a negative one:

we found that the transcriptomes of circulating monocytes in QFS patients are not grossly different from those of healthy controls, asymptomatic Q fever seropositive controls, and CFS patients.

Of the two genes they found that were a bit different, the peptides they code for were either present in the same amount (MOT-c) or not convincingly different from the two control cohorts (humanin).

I didn't really follow all the washing of the cells and other preparatory processes including stimulation with LPS. Maybe part of the problem is that they washed away a substance that might have made the cells perform differently? Maybe they need to be using tissue cells rather than blood cells?

Anyway, I don't think there is much to get excited about here, at least yet. Good on them for poking about in the biology, but the reflexive reaching for a 'psychological incentive' explanation when they don't know what is going on doesn't inspire confidence.

The fact that some acute Q fever patients remain fatigued following their infection could suggest that a concomitant, perhaps psychological, incentive is needed to induce a clinical chronic fatigue syndrome.

 

[duncan]

Interesting that the proportion who, in effect, remain sick is 20%. Again.