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Can the light of immunometabolism cut through “brain fog”?
Mady Hornig
Mady Hornig
Published February 10, 2020
Citation Information: J Clin Invest. 2020;130(3):1102-1105. https://doi.org/10.1172/JCI134985.
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Commentary

Can the light of immunometabolism cut through “brain fog”?

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Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a highly debilitating disease with heterogeneous constitutional and neurological complaints. Infection-like symptoms often herald disease onset, but no pathogen or immune defect has been conclusively linked. In this issue of the JCI, Mandarano et al. illuminate bioenergetic derangements of ME/CFS T cell subsets. CD4+ and CD8+ T cells had impaired resting glycolysis. CD8+ cells additionally showed activation-related metabolic remodeling deficits and decreased mitochondrial membrane potential; a subset had increased resting mitochondrial mass. Immune senescence and exhaustion paradigms offer only partial explanations. Hence, unique mechanisms of disrupted immunometabolism may underlie the complex neuroimmune dysfunction of ME/CFS.

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Mady Hornig

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Figure 1

A model of potential metabolic and mitochondrial derangements in CD4+ and/or CD8+ T cell subsets from patients with ME/CFS.

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A model of potential metabolic and mitochondrial derangements in CD4+ an...
Affected T cells show (i) deficits in basal glycolysis that may interplay with (ii) abnormalities in mitochondrial metabolism, with decreased proton leak at rest and reduced ATP production in the CD8+ subset upon activation. (iii) Resting and activated CD8+ cells also show decreased mitochondrial membrane potential, and a resting CD8+ subset may display increased mitochondrial mass. Alterations in factors that have been previously shown (red) suggest that deficits in bioenergetics, metabolic reprogramming, and mitochondrial dynamics may vary across more specific CD4+ and CD8+ T cell subsets, including subsets with features of immune aging, senescence, or exhaustion (3, 4, 7–10, 15, 16). FAO, fatty acid oxidation; MAVS, mitochondrial antiviral signaling protein; mtROS, mitochondrial reactive oxygen species; NAD+, nicotinamide adenine dinucleotide; NLRP3, NOD-, LRR- and pyrin domain–containing protein 3 (inflammasome); OXPHOS, oxidative phosphorylation; RIG-I, retinoic acid–inducible gene I; SIRT3, NAD-dependent deacetylase sirtuin-3; TCA, tricarboxylic acid cycle; TGF-β, transforming growth factor β; Trp, tryptophan.

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