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Table 4 Summary of primary outcome results

From: A systematic review of mitochondrial abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease

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)
  1. ADP adenosine diphosphate, ATP adenosine triphosphate, CoQ10 Coenzyme Q10, DNA deoxyribonucleic acid, HC healthy control, mtDNA mitochondrial deoxyribonucleic acid, ME/CFS/SEID myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disorder, NK natural killer, NMR nuclear magnetic resonance, OCR oxygen consumption rate, PBMCs peripheral blood mononuclear cells; RNA ribonucleic acid, SNPs single nucleotide polymorphisms, TRPM3 transient receptor potential melastatin 3, TCA tricarboxylic acid, 2-APB 2-aminoethoxydiphenyl borate
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