Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations

Mandarano, Alexandra H; Maya, Jessica; Giloteaux, Ludovic; Peterson, Daniel L.; Maynard, Marco; Gottschalk, Claudius; Hanson, Maureen R.

doi:10.1172/jci132185

Cited by 98 publications

(155 citation statements)

References 63 publications

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“…We found that both Mitotracker Red fluorescence (p=0.02) and the mitochondrial membrane potential (Δψm) were reduced in ME/CFS lymphoblasts ( Figure 6B, Figure S9 Panel 1B). Similar findings were recently reported for CD4 + and CD8 + T-cells [15].…”

Section: Error Bars Represent Standard Errors Of the Mean (A) Mitochsupporting

confidence: 92%

“…Previous steady state measurements and metabolic flux measurements of mitochondrial respiratory function in ME/CFS lymphocytes have suggested that in ME/CFS cells there is either a generalized reduction [6][7][8] or little change [9,15] in mitochondrial activity and respiratory capacity. However, functionally normal OXPHOS Complex I to IV activity has also been reported in ME/CFS lymphocytes [11,47], while the expression of mitochondrial proteins is upregulated in patient saliva, platelets and lymphocytes [12,13,30].…”

Section: Discussionmentioning

confidence: 99%

“…Most recently, glycolytic rates were reported to be reduced in ME/CFS CD4 + and CD8 + Tcells [15]. To investigate glycolysis in intact ME/CFS lymphoblasts, we modified and implemented an optimized Seahorse assay to assess real-time glycolytic production of lactate in live cells by measuring the extracellular acidification rate (ECAR) of the medium.…”

Section: Glycolytic Rates Are Unaffected In Me/cfs Lymphoblasts But mentioning

confidence: 99%

“…given the more highly reduced state of the carbons in fatty acid chains compared to those in sugar molecules. ME/CFS cells could shift their metabolism in favour of fatty acid  oxidation because of a deficiency in glycolysis [15,16] or pyruvate dehydrogenase which partially oxidizes pyruvate and supplies acetyl CoA to the TCA cycle [17]. It has also been suggested that in ME/CFS cells metabolism shifts away from glycolysis in favour of the pentose phosphate pathway which can oxidize sugars in the cytosol to generate reducing power that can be transported into the mitochondria to drive electron transport [34].…”

Section: One Of the Key Upstream Regulators Of Mitochondrial Protein mentioning

confidence: 99%

“…Mitochondrial respiratory function in ME/CFS neutrophils [6,7] and peripheral blood mononuclear cells (PBMCs) is reportedly reduced [8] or unchanged [9], yet the oxidative phosphorylation (OXPHOS) complexes appear normal [10,11], while the expression of genes encoding mitochondrial proteins in patient saliva, platelets, and lymphocytes is elevated [12][13][14]. Most recently, mitochondrial respiration was found to be unchanged in resting and stimulated CD4 + and CD8 + T cells, with the sole exceptions of a small reduction in the proton leak in resting and ATP synthesis in stimulated CD8 + cells [15].…”

Section: Introductionmentioning

confidence: 99%

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An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients

Missailidis¹,

Annesley²,

Allan³

et al. 2020

Preprint

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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or “PEM”), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the fatigue-inducing activity. There is no definitive molecular marker or known underlying pathological mechanism for the condition. Increasing evidence for aberrant energy metabolism suggests a role for mitochondrial dysfunction in ME/CFS. Our objective was therefore to measure mitochondrial function and cellular stress sensing in actively metabolising patient blood cells. We immortalized lymphoblasts isolated from 51 ME/CFS patients diagnosed according to the Canadian Consensus Criteria and an age- and gender-matched control group. Parameters of mitochondrial function and energy stress sensing were assessed by Seahorse extracellular flux analysis, proteomics, and an array of additional biochemical assays. As a proportion of the basal oxygen consumption rate (OCR), the rate of ATP synthesis by Complex V was significantly reduced in ME/CFS lymphoblasts, while significant elevations were observed in Complex I OCR, maximum OCR, spare respiratory capacity, nonmitochondrial OCR and “proton leak” as a proportion of the basal OCR. This was accompanied by a reduction of mitochondrial membrane potential, chronically hyperactivated TOR Complex I stress signalling and upregulated expression of mitochondrial respiratory complexes, fatty acid transporters and enzymes of the β-oxidation and TCA cycles. By contrast, mitochondrial mass and genome copy number, as well as glycolytic rates and steady state ATP levels were unchanged. Our results suggest a model in which ME/CFS lymphoblasts have a Complex V defect accompanied by compensatory upregulation of their respiratory capacity that includes the mitochondrial respiratory complexes, membrane transporters and enzymes involved in fatty acid β-oxidation. This homeostatically returns ATP synthesis and steady state levels to “normal” in the resting cells, but may leave them unable to adequately respond to acute increases in energy demand as the relevant homeostatic pathways are already activated.

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Section: Error Bars Represent Standard Errors Of the Mean (A) Mitochsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Glycolytic Rates Are Unaffected In Me/cfs Lymphoblasts But mentioning

confidence: 99%

Section: One Of the Key Upstream Regulators Of Mitochondrial Protein mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients

Missailidis¹,

Annesley²,

Allan³

et al. 2020

Preprint

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Electroacupuncture at BL15 attenuates chronic fatigue syndrome by downregulating iNOS/NO signaling in C57BL/6 mice

Zhu

Wang

Yao

et al. 2022

The Anatomical Record

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Chronic fatigue syndrome (CFS) has a high incidence due to the increased pressure of daily life and work in modern society. Our previous clinical studies have found the effects of electroacupuncture (EA) on CFS patients, however, the mechanism of EA on CFS is still unknown. In this study, we investigated the effects of EA on cardiac function in a CFS mouse model to explore its underlying mechanism. The mice were randomly divided into three groups: control, CFS, and CFS mice receiving EA (CFS + EA). After behavioral assessments and echocardiographic measurement, blood and heart tissue of the mice were collected for biochemical tests, and then we evaluated the effects of EA on the CFS mouse model when nitric oxide (NO) levels were enhanced by l‐arginine. The results showed that EA ameliorated the injured motor and cardiac function. Meanwhile, EA also inhibited increased expression of inducible nitric oxide synthase (iNOS) at heart tissue and the serum NO levels in mice subjected to sustained forced swimming stress. Furthermore, the NO level in serum increased with l‐arginine administration, which blocked the effects of EA on CFS mice. This study suggested that EA could improve the motor function and cardiac function in CFS mice and its effects may be associated with the down‐regulation of iNOS/NO signaling.

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Nervous system‐related tropism of SARS‐CoV‐2 and autoimmunity in COVID‐19 infection

Weissert

2023

Eur J Immunol

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The effects of SARS‐CoV‐2 in COVID‐19 on the nervous system are incompletely understood. SARS‐CoV‐2 can infect endothelial cells, neurons, astrocytes, and oligodendrocytes with consequences for the host. There are indications that infection of these central nervous system‐resident cells may result in long term effects, including emergence of neurodegenerative diseases. Indirect effects of infection with SARS‐CoV‐2 relate to the induction of autoimmune disease involving molecular mimicry or/and bystander activation of T‐ and B cells and emergence of autoantibodies against various self‐antigens. Data obtained in preclinical models of coronavirus induced disease gives important clues for understanding of nervous system related assault of SARS‐CoV‐2. The pathophysiology of long‐COVID syndrome and post‐COVID syndrome in which autoimmunity and immune dysregulation might be the driving forces are still incompletely understood. Better understanding of nervous‐system‐related immunity in COVID‐19 might support development of therapeutic approaches. In this review, the current understanding of SARS‐CoV‐2 tropism for the nervous system, the associated immune responses and diseases are summarized. The data indicates that there is viral tropism of SARS‐CoV‐2 for the nervous system resulting into various disease conditions. Prevention of SARS‐CoV‐2 infection by means of vaccination is currently the best strategy for prevention of subsequent tissue damage involving the nervous system.This article is protected by copyright. All rights reserved

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Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations

Cited by 98 publications

References 63 publications

An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients

An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients

Electroacupuncture at BL15 attenuates chronic fatigue syndrome by downregulating iNOS/NO signaling in C57BL/6 mice

Nervous system‐related tropism of SARS‐CoV‐2 and autoimmunity in COVID‐19 infection

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