Dysregulated provision of oxidisable substrates to the mitochondria in ME/CFS lymphoblasts, by Daniel Missailidis, Oana Sanislav, Claire Y Allan, Paige K. Smith, Sarah J Annesley, and Paul R Fisher in Int. J. Mol. Sci. 2021, 22(4), 2046; 19 February 2021 [doi.org/10.3390/ijms22042046] (This article belongs to the Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures 2.0)
Research abstract:
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.
The meaning of recovery differed between participants—expectations for improvement and deployment of the sick role (and associated stigma) were key influences. While some saw recovery as complete freedom from symptoms, many defined it as freedom from the “
The purpose of the present study was to investigate the safety and tolerability of the 
Objective:
When it was becoming clear that COVID-19 was a serious issue early last year, Nina Muirhead (pictured) had a strong suspicion about what would happen next.
meets the criteria for CFS/ME. The patient and patient’s parents reported 6 months of fatigue, which was not improved even after an adequate period of sleep and very low physical performance. According to the parents, the patient has difficulty concentrating, is morose most of the day and reports limb twitching and paraesthesia.
Outpatient assessment of a patient with fatigue and chronic pain can be challenging. This is particularly the case when the patient is polysymptomatic and they have had many interactions with healthcare professionals before. It is all too easy to ‘admit defeat’ as in Dr A’s case, or initiate a test or another referral in ‘response’ to every symptom described by the patient during the course of their illness (Dr B). How can this be avoided?
