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Article

Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts

1
Department of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Melbourne, VIC 3086, Australia
2
Monash Health, Melbourne, VIC 3186, Australia
*
Author to whom correspondence should be addressed.
Academic Editor: Daniela Caccamo
Int. J. Mol. Sci. 2021, 22(4), 2046; https://doi.org/10.3390/ijms22042046
Received: 16 January 2021 / Revised: 8 February 2021 / Accepted: 15 February 2021 / Published: 19 February 2021
Although understanding of the biomedical basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is growing, the underlying pathological mechanisms remain uncertain. We recently reported a reduction in the proportion of basal oxygen consumption due to ATP synthesis by Complex V in ME/CFS patient-derived lymphoblast cell lines, suggesting mitochondrial respiratory inefficiency. This was accompanied by elevated respiratory capacity, elevated mammalian target of rapamycin complex 1 (mTORC1) signaling activity and elevated expression of enzymes involved in the TCA cycle, fatty acid β-oxidation and mitochondrial transport. These and other observations led us to hypothesise the dysregulation of pathways providing the mitochondria with oxidisable substrates. In our current study, we aimed to revisit this hypothesis by applying a combination of whole-cell transcriptomics, proteomics and energy stress signaling activity measures using subsets of up to 34 ME/CFS and 31 healthy control lymphoblast cell lines from our growing library. While levels of glycolytic enzymes were unchanged in accordance with our previous observations of unaltered glycolytic rates, the whole-cell proteomes of ME/CFS lymphoblasts contained elevated levels of enzymes involved in the TCA cycle (p = 1.03 × 10−4), the pentose phosphate pathway (p = 0.034, G6PD p = 5.5 × 10−4), mitochondrial fatty acid β-oxidation (p = 9.2 × 10−3), and degradation of amino acids including glutamine/glutamate (GLS p = 0.034, GLUD1 p = 0.048, GOT2 p = 0.026), branched-chain amino acids (BCKDHA p = 0.028, BCKDHB p = 0.031) and essential amino acids (FAH p = 0.036, GCDH p = 0.006). The activity of the major cellular energy stress sensor, AMPK, was elevated but the increase did not reach statistical significance. The results suggest that ME/CFS metabolism is dysregulated such that alternatives to glycolysis are more heavily utilised than in controls to provide the mitochondria with oxidisable substrates. View Full-Text
Keywords: Myalgic Encephalomyelitis; ME/CFS; mitochondria; metabolism; transcriptomics; proteomics; beta-oxidation; amino acid catabolism; glycolysis; TCA cycle Myalgic Encephalomyelitis; ME/CFS; mitochondria; metabolism; transcriptomics; proteomics; beta-oxidation; amino acid catabolism; glycolysis; TCA cycle
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MDPI and ACS Style

Missailidis, D.; Sanislav, O.; Allan, C.Y.; Smith, P.K.; Annesley, S.J.; Fisher, P.R. Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts. Int. J. Mol. Sci. 2021, 22, 2046. https://doi.org/10.3390/ijms22042046

AMA Style

Missailidis D, Sanislav O, Allan CY, Smith PK, Annesley SJ, Fisher PR. Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts. International Journal of Molecular Sciences. 2021; 22(4):2046. https://doi.org/10.3390/ijms22042046

Chicago/Turabian Style

Missailidis, Daniel, Oana Sanislav, Claire Y. Allan, Paige K. Smith, Sarah J. Annesley, and Paul R. Fisher. 2021. "Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts" International Journal of Molecular Sciences 22, no. 4: 2046. https://doi.org/10.3390/ijms22042046

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