A possible role for mitochondrial-derived peptides humanin and MOTS-c in patients with Q fever fatigue syndrome and chronic fatigue syndrome

Abstract

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. Electronic supplementary material The online version of this article (10.1186/s12967-019-1906-3) contains supplementary material, which is available to authorized users.

Multi-omics Examination of Q Fever Fatigue Syndrome Identifies Similarities with Chronic Fatigue Syndrome

“…During the Dutch Q fever outbreak (2009-2012), our group demonstrated that QFS patients exhibit signs of altered immunity through the monocyte-derived cytokines Tumor Necrosis Factor (TNF)α, interleukin (IL)-1β, and especially IL-6, together with the interferon (IFN)γ-axis (12)(13)(14). In addition, we found that monocytes of both QFS patients and CFS patients show decreased expression of mitochondrial derived peptide (MDP)-coding genes MT-RNR1 and MT-RNR2, resulting in a decreased production of humanin (MT-RNR2) (15).…”

“…Dennis et al showed that the 4E-BP1 phosphorylation was inhibited when intracellular adenosine triphosphate (ATP) levels were lowered (48). Interestingly, chronic fatigue has previously been associated with a decrease in cell metabolism (15,18,49,50), and PBMCs of CFS patients showed a decrease in mitochondrial function compared to PBMCs of HC when stressed (51)(52)(53). Axis inhibition protein (AXIN1), negatively regulates the Wnt signalling pathway by downregulation of β-catenin (54), but has also been identi ed as a scaffold protein that activates TGF-β signalling (55).…”

“…One could speculate that such a mechanism contributes to changes in in ammation in QFS patients and CFS patients, and that the observed in ammation is secondary to metabolic alterations. As our group recently showed that monocytes of QFS patients and CFS patients exhibit a decreased expression of MDP-coding genes MT-RNR1 and MT-RNR2 compared to HC (15), it would be interesting to investigate the role of these MDP-coding peptides in these metabolic and in ammatory alterations.…”

Multi-omics examination of Q fever fatigue syndrome identifies similarities with chronic fatigue syndrome

“…Dennis et al showed that the 4E-BP1 phosphorylation was inhibited when intracellular adenosine triphosphate (ATP) levels were lowered (48). Interestingly, chronic fatigue has previously been associated with a decrease in cell metabolism (15,18,49,50), and PBMCs of CFS patients showed a decrease in mitochondrial function compared to PBMCs of HC when stressed (51)(52)(53). Axis inhibition protein (AXIN1), negatively regulates the Wnt signalling pathway by downregulation of β-catenin (54), but has also been identi ed as a scaffold protein that activates TGF-β signalling (55).…”

Long-Lasting Transcriptional Changes in Circulating Monocytes of Acute Q Fever Patients

“…Based on recent findings by our group [16] identifying a significantly decreased expression of mitochondrial-derived peptide (MDP)-coding genes MT-RNR1 and MT-RNR2 in QFS patients compared with healthy controls, we investigated the expression of these genes in acute Q fever patients compared with healthy controls, both at the time of infection and follow-up.…”