biomolecules: Bioenergetic and Proteomic Profiling of Immune Cells in ME/CFS Patients: An Exploratory Study - Fernandez-Guerra et al - 2021

[Kalliope]

biomolecules: Bioenergetic and Proteomic Profiling of Immune Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients: An Exploratory Study
Fernandes-Guerra et al

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous, debilitating, and complex disease.

Along with disabling fatigue, ME/CFS presents an array of other core symptoms, including autonomic nervous system (ANS) dysfunction, sustained inflammation, altered energy metabolism, and mitochondrial dysfunction.

Here, we evaluated patients' symptomatology and the mitochondrial metabolic parameters in peripheral blood mononuclear cells (PBMCs) and plasma from a clinically well-characterised cohort of six ME/CFS patients compared to age- and gender-matched controls.

We performed a comprehensive cellular assessment using bioenergetics (extracellular flux analysis) and protein profiles (quantitative mass spectrometry-based proteomics) together with self-reported symptom measures of fatigue, ANS dysfunction, and overall physical and mental well-being.

This ME/CFS cohort presented with severe fatigue, which correlated with the severity of ANS dysfunction and overall physical well-being. PBMCs from ME/CFS patients showed significantly lower mitochondrial coupling efficiency.

They exhibited proteome alterations, including altered mitochondrial metabolism, centred on pyruvate dehydrogenase and coenzyme A metabolism, leading to a decreased capacity to provide adequate intracellular ATP levels.

Overall, these results indicate that PBMCs from ME/CFS patients have a decreased ability to fulfill their cellular energy demands.

 

[Londinium]

This field is crying out for replication studies and (to my untrained, somewhat uninformed try) this is yet another study finding similar mitochondrial issues. Anyone got a good overview of these studies / seen a good review paper? Would be good to compare results / where in the ATP production process issus have been found / what types of cells were tested.

 

[glennthefrog]

time and time again the same results, and nothing ever changes for us... we're still being treated as hypochondriacs and hysterical when some 8000 studies show that our bodies are a complete wreck, specially in regard to energy producing cellular systems . I just don't understand anymore what the point of these studies is, nothing ever, ever changes for us. So tired and frustrated...

 

[Hutan]

Small (6 patients) Danish study.
It's free access - you can download the pdf.

Paula Fernandez-Guerra
Ana C. Gonzalez-Ebsen
Susanne E. Boonen
Julie Courraud
Niels Gregersen
Jesper Mehlsen
Johan Palmfeldt
Rikke K. J. Olsen
Louise Schouborg Brinth

Aarhus University, Odense University Hospital, University of Southern Denmark, Statens Serum Institute, Rigshospitalet, Nordsjaellands Hospital

Looks to be nicely written up and minimal BPS overall.

All patients enrolled in the study were evaluated for the following diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Fukuda Criteria [5], Revised Canadian Criteria [49], International Consensus Criteria (ICC) [50], and American Institute of Medicine (IOM) criteria [3] (Table S1). All six patients fulfilled the Fukuda Criteria, five the ICC and OIM criteria, and four the Revised Canadian Criteria.

So, one of the six was just Fukuda compliant - so not clear if they have PEM.

These evaluations were supple- mented with three self-assessed questionnaires of well-being: Fatigue Scale of Motor and Cognitive function (FSMC), Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and COMPASS-31. FSMC evaluates fatigue symptoms by providing a global fa- tigue severity score as well as subscales of motor and mental fatigue [39]. SF-36 is a questionnaire that evaluates the health-related quality of life [40]. COMPASS-31 specifies and quantifies symptoms and severity of autonomic dysfunction [41].

The Fatigue Scale of Motor and Cognitive function could be worth checking out further.

Comparison of bioenergetics parameters showed no significant differences in glycolysis between patients and controls (Table S4). However, we observed differences in mitochondrial respiration, specifically, coupling efficiency (FC = 0.87, p-value 0.041) (Figure 2a–f). No other differences were observed in the remaining parameters of bioenergetics profiling (Figure 2). Coupling efficiency correlated
negatively with disease duration (r = -0.84, p-value = 0.005) and positively with SF-36 gen- eral health score (r = 0.86, p-value = 0.003) (Figure 2g–h). No significant correlation was observed between coupling efficiency and FSMC or COMPASS-31 (Table S5).

The list of proteins found to be different in this very small sample is interesting:

The two most significantly altered proteins in PBMCs from ME/CFS patients are related to the immune system, cathepsin W (CTSW) (FC = 1.53), involved in the major histocompatibility complex (MHC) class I pathway, and human leukocyte antigen (HLA) protein histocompatibility antigen, alpha chain E, (HLA-E) (FC = 1.34) belonging to the MHC class Ib.

In contrast, mixed lineage kinase domain-like protein (MLKL) (FC = 0.89), which plays a critical role in tumour necrosis factor (TNF)-induced necroptosis, was sig- nificantly lower in ME/CFS patients than controls,verall, indicating an alteration of the immune response in ME/CFS patients. The third most significantly altered protein was LAMTOR1 (FC = 1.32).

LAMTOR1, together with mildly higher levels of LAMTOR5 (FC = 1.1, p-value = 0.03), reflect increased levels of the ragulator complex that recruits mam- malian target of rapamycin complex 1 (mTORC1) to the lysosomes for activation. Overall, this indicates that mTORC1 could be more active in PBMCs from ME/CFS patients.

Here's a bit explaining coupling efficiency and also explaining that we aren't yet getting overwhelming agreement on what is happening in ME/CFS mitochondria, with different techniques perhaps explaining different findings.

Coupling efficiency is a tightly regulated process that represents how much ATP is produced per molecule of ox- ygen. The lower coupling efficiency observed leads to a lower ATP production and could be related to the slightly higher proton leakage seen in the patients' cells. We also observed a tendency of higher spare respiratory capacity reflecting how much of the maximal res- piration is being used by the cells. This higher spare respiratory capacity could be a compensatory mechanism producing more mitochondrial ATP, especially under stress condi- tions such as higher physical or mental activity. However, we observed a tendency of de- creased ATP-linked to maximal respiration, indicating that PBMCs from ME/CFS patients cannot produce as much ATP as the controls even with increased spare respiratory capac- ity.

Similar to our study, immortalised lymphocytes from ME/CFS patients have shown increases in proton leakage and spare respiratory capacity with non-significant changes in basal respiration [31], whereas another study on PBMCs from ME/CFS patients has shown no differences in coupling efficiency and a lower spare respiratory capacity [34]. This discrepancy can be due to technical differences in the protocols used to measure mi- tochondrial respiration. This previous study used frozen PBMCs, while we used fresh PBMCs, and the third study used immortalised cells. These different procedures could lead to changes in mitochondrial respiration. Moreover, we used a modified protocol to avoid the sequential injections of oligomycin and FCCP that can lead to underestimation of the maximal respiration and spare respiratory capacity [61]. This incongruity can also be explained by the heterogeneity of the ME/CFS population and reflects the importance of replicating biomarker studies in independent patient cohorts to validate their diagnos- tic sensitivity or usefulness for subgrouping of patients in future research studies.

@DMissa

 

[Hoopoe]

A subunit the mitochondrial complex V was also abnormal. That's similar to the complex V inefficiency previously reported.

 

[Snow Leopard]

Here's a bit explaining coupling efficiency and also explaining that we aren't yet getting overwhelming agreement on what is happening in ME/CFS mitochondria, with different techniques perhaps explaining different findings.

The biggest problem with studies like this is the assumption that patterns of glycolysis or mitochondrial respiration in PBMCs is somehow relevant, despite the fact that the microenvironment for PBMCs is quite different to other tissue types.

 

[EducateME]

What do you think about this paper which opens up new hypotheses in the understanding of neuronal bioenergetics: Efficient extra-mitochondrial aerobic ATP synthesis in neuronal membrane systems - PubMed (nih.gov)

 

[borko2100]

Ok so now multiple studies are showing a similar mitochondrial problem. Seems to me like normal energy production is impaired so we rely on backup energy systems (see mtor upregulation). Maybe, due to the inefficiency of those systems and the fact that they are meant to only be auxiliary and thus used sparingly, their overuse (as a result of intense physical / mental stimulation) leads to the production of damaging substances or direct cellular damage resulting in PEM?

 

[Ravn]

The Fatigue Scale of Motor and Cognitive function could be worth checking out further.

FSMC can be accessed here. Not perfect but better than some I've seen.
https://www.sralab.org/sites/default/files/2017-06/Questionnaire_Kappos_et_al.php1_.pdf

 

[Midnattsol]

Posts on how members have learned science have been moved to the thread An ME friendly way to learn science?.