Table 4 Summary of primary outcome results
Author (date) | Technique | Sample | Findings |
|---|---|---|---|
Armstrong et al. 2015 | NMR spectroscopy | Whole blood, urine | Twenty-nine metabolites in blood and thirty metabolites in urine were identified. The absolute concentrations of six blood metabolites were significantly different following NMR analysis. Glucose levels were increased (p = 0.011) in ME/CFS/SEID patients compared with HC. Whereas acetate (p = 0 = 0.04), glutamate (p = 0.029), hypoxanthine (p = 0.001), lactate (p = 0.006) and phenylalanine (p = 0.001) were decreased in ME/CFS/SEID patients compared with HC. Metabolites analysed as a function of total metabolite concentrations reported six metabolites that were significantly different. For this analysis aspartate (p = 0.049) and glucose (p = 0.002) were increased whereas glutamate (p = 0.036), hypoxanthine (p = 0.003), lactate (p = 0.004) and phenylalanine (p = 0.003) were decreased. The absolute concentrations of five urinary metabolites were significantly different in ME/CFS/SEID patients compared with non-ME/CFS/SEID controls using NMR analysis. All urinary absolute concentration metabolites were decreased: acetate (p = 0.003); alanine (p = 0.049); formate (p = 0.002); pyruvate (p = 0.034) and serine (p = 0.034). Eight metabolites were significantly different within relative abundance data. These metabolites were decreased in ME/CFS/SEID patients compared with HC: acetate (p = 0.025); alanine (p = 0.008); formate (p = 0.026); pyruvate (p = 0.001); serine (p = 0.008); valine (p = 0.026). While allantoin (p = 0.011) and creatinine (p = 0.025) were increased |
Billing-Ross et al. 2016 | Illumina sequencing | DNA | No significant association between mtDNA SNPs and ME/CFS/SEID status compared to HC participants were found. Haplogroups J, U and H (p < 0.01) in addition to eight other SNPs (p < 0.05) were positively correlated with symptoms, symptom clusters or symptom severity in ME/CFS/SEID patients. Overall, heteroplasmy frequency was low in both groups |
Booth et al. 2012 | ATP profile test | Neutrophils | Using the ATP profile test ME/CFS/SEID patients were found to have measurable mitochondrial disfunction including: ATP availability and oxidative stress efficiency compared to HC participants. No p- value provided |
Castro-Marrero et al. 2013 | Western blot bioluminescence assay | PBMCs | ME/CFS/SEID patients had significantly lower levels of CoQ10 (p < 0.001) and ATP (p < 0.001) and higher levels of lipid peroxidation (p < 0.001) compared to HC participants. Mitochondrial citrate synthase activity and expression levels of mitochondrial DNA content, peroxisome proliferator-activated receptor gamma-coactivator 1-alpha and transcription factor A were not significantly different between the two groups |
Germain et al. 2017 | Mass spectrometry | Whole blood | 74 out of 361 metabolites including energy- related compounds, glucose and oxaloacetate were differentially accumulated in ME/CFS/SEID patients compared to HC participants (p < 0.05). Purines such as ADP and ATP, pyrimidines and many amino acid metabolic pathways were not significantly different between the groups |
Light et al. 2013 | Real time QPCR | Leukocytes | ME/CFS/SEID patients presented with higher P2X purinoceptor 7 (p = 0.007) and lower Heat Shock Protein Family A (p = 0.032) compared to HC participants. Diazepam binding inhibitor, the gamma-aminobutyric acid A receptor modulator correlated with disease severity for ME/CFS/SEID patients (r = − 0.34, p < 0.05) |
Maes et al. 2009 | High performance liquid chromatography | Plasma | Compared to HC participants, ME/CFS/SEID patients had significantly lower plasma CoQ10 (p < 0.001). There was a negative correlation between CoQ10 levels and total scores on the FF scale (r = − 0.28, p = 0.03), fatigue (r = − 0.86, p < 0.001) and autonomic symptoms (r = − 0.36, p = 0.005) |
Mandarano et al. 2019 | Seahorse XFe96 Flow cytometry Confocal microscopy | T cells | CD8+ T cells belonging to ME/CFS/SEID patients had lower mitochondrial membrane potential (p < 0.01), proton leak (p < 0.05) and ATP production (p < 0.05) compared to HC participants. Glycolysis at rest was lower in CD8+ and CD4+ cells from ME/CFS/SEID patients (p < 0.05) |
Missailidis et al. 2020A | MitoTracker Green FM Seahorse XFe24 (mitochondrial stress test) | Lymphoblasts | ME/CFS/SEID lymphoblasts showed significantly less activation of ATP synthesis by complex V (p = 0.004), mitochondrial membrane potential (p = 0.024), hyperactivated TOR complex 1 stress signalling (p < 0.001) and greater activation of Complex 1 OCR (p = 0.005), maximum OCR (p = 0.002), spare respiratory capacity (p = 0.024), nonmitochondrial OCR (p = 0.002), enzymes of β-oxidation (p < 0.001) and TCA cycles (p = 0.004) as well as proton leak (p = 0.006) compared to HC participants. There was no difference in mitochondrial mass, genome copy number, glycolytic rates and steady state ATP levels between the two groups |
Missailidis et al. 2020B | Seahorse XFe24 (mitochondrial stress test) XF glycolysis stress test | PBMCs, Lymphoblasts | Recovered lymphocytes from frozen storage death rate, mitochondrial respiratory function and TORC1 activity can be used as an effective biomarker for ME/CFS/SEID with 90% sensitivity. ME/CFS/SEID patients had a greater lymphocyte death rate compared to HC participants (p < 0.001). Mitochondrial membrane potential, the rate of O2 consumption (OCR) by ATP synthesis and the proton leak, the maximum OCR by uncoupled mitochondria, the uncoupled activity of Complex I and the non-mitochondrial OCR values were effectively able to discriminate ME/CFS/SEID patients to HC participants (p < 0.001). The phosphorylation state of TORC1 Kinase Substrate, 4E-BP1can also be used to differentiate between patient and HC groups (p < 0.001) |
Naviaux et al. 2016 | Hydrophilic interaction liquid chromatography, electrospray ionization, and tandem mass spectrometry | Plasma | Abnormalities in 20 metabolic pathways out of 63 were found in ME/CFS/SEID patients compared to HC participants; this includes, purine (p = 0.044), cholesterol (p = 0.035), pyrroline-5-carboxylate (p = 0.014), riboflavin (p = 0.005) and branch chain amino acid (p = 0.023) metabolism. No p value was recorded |
Nguyen et al. 2016 | Flow cytometry | NK cells, B lymphocytes | Compared to HC participants, ME/CFS/SEID patients were found to have reduced TRPM3 surface expression on CD19+ B cells and CD56bright NK cells (p < 0.05). CD56bright NK cells exposed to 2-APB and thapsigargin had significantly decreased cytoplasmic calcium (p < 0.05) |
Nguyen et al. 2019 | Seahorse XFp | NK cells | Compared to HC participants, glycolytic reserve in resting NK cells were significantly lower in ME/CFS/SEID patients (p < 0.05). There was no difference in mitochondrial respiration between the two groups |
Plioplys and Plioplys 1995 | Electron microscopy | Percutaneous needle muscle biopsies | There were no significant mitochondrial abnormalities found between ME/CFS/SEID patients and HC participants including: subsar- colemmal mitochondrial aggregates, intermyofibrillar mitochondrial aggregates, mitochondrial circumference, area, pleomorphism or compartmentalization of the inner mitochondrial membrane |
Shungu et al. 2012 | Magnetic resonance spectroscopy | Cerebrospinal fluid | No significant differences in high energy phosphate metabolites including, ATP, creatine phosphate (PCr) and inorganic phosphate (Pi), were found between ME/CFS/SEID patients and HC participants |
Sweetman et al. 2019 | RNA sequencing | PBMCs | Significantly increased gene transcripts important for mitochondrial function, including PMAIP1, PMPCB and JUN, were found in ME/CFS/SEID patients compared to HC participants (p < 0.001) |
Tomas et al. 2017 | Seahorse XFp | PBMCs | ME/CFS/SEID patients had significantly lower oxidative phosphorylation parameters including: basal respiration (p ≤ 0.005), ATP production (p ≤ 0.005), proton leak (p ≤ 0.005), maximal respiration (p ≤ 0.05), reserve capacity (p ≤ 0.005), non-mitochondrial respiration (p ≤ 0.005), and coupling efficiency (p ≤ 0.005). Glycolytic activity did not significantly differ between the two groups. |
Venter et al. 2019 | DNA sequencing | mtDNA | Majority of the severely affected and moderately affected patient groups from South Africa and the United Kingdom did not have a mildly deleterious population variant. Haplogroup distributions and heteroplasmy analysis did not detect any variations of significance between ME/CFS/SEID patients and HC participants across both population groups |
Yamano et al. 2016 | Agilent CE capillary electrophoresis system | Plasma | Compared to HC participants, ME/CFS/SEID patients exhibited significantly higher intermediate metabolite concentrations including: ornithine/citrulline, pyruvate/isocitrate ratios in the tricarboxylic acid (TCA) and urea cycles (p < 0.001) |