TiredMathematician
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mTORC1 dysregulation and context-dependent mitochondrial dysfunction in ME/CFS: a mechanistic and translational review
Sunseri, Anthony; Gaudreault, Roger; Retornaz, Frédérique
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a common, debilitating, multisystemic disease whose cardinal symptom is post-exertional malaise (PEM). PEM is a delayed and sustained exacerbation of symptoms following physical, cognitive, emotional, or orthostatic stress. The timing of PEM suggests it is less a constant energy deficiency than a failure in the transition between energy mobilization, cellular recycling, and recovery.
This review evaluates the mechanistic target of rapamycin complex 1 (mTORC1) as a dynamic control point that may link mitochondrial signaling, immunometabolism, inflammation, autophagy, and the post-exertional response. Human data directly related to mTORC1 remain scarce and are based primarily on the phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) in lymphoblasts and on the increase in Ragulator complex proteins in peripheral blood mononuclear cells.
Metabolomic, bioenergetic, immune, neurovascular, intestinal, and autophagic observations also provide functional convergence, although they do not constitute direct evidence of mTORC1 hyperactivation. Analysis of the literature data points to context-dependent mitochondrial dysfunction: the mitochondrial apparatus may appear relatively intact at rest, whereas substrate utilization, respiratory reserve, quality control, and the return to homeostasis become insufficient under stress. Thus, mTORC1 could act as a transition switch when energy stress is expected to promote autophagy, mitophagy, and recovery.
The exploratory signal obtained with rapamycin reinforces the value of mechanistic intervention, pending therapeutic validation. This hypothesis must be tested through longitudinal studies following standardized stimulation, with coordinated measurements of mTORC1 signaling, the AMP-activated protein kinase (AMPK)–Unc-51-like kinase 1 (ULK1) axis, autophagic flux, and respiratory reserve for up to 48 h.
A better understanding of the pathophysiology of PEM in ME/CFS could lead to therapeutic advances in this common and debilitating condition for which no specific treatment is currently available. mTORC1 may act as a transition switch when energy stress should promote autophagy, mitophagy, and recovery.
Web | DOI | Journal of Translational Medicine
Sunseri, Anthony; Gaudreault, Roger; Retornaz, Frédérique
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a common, debilitating, multisystemic disease whose cardinal symptom is post-exertional malaise (PEM). PEM is a delayed and sustained exacerbation of symptoms following physical, cognitive, emotional, or orthostatic stress. The timing of PEM suggests it is less a constant energy deficiency than a failure in the transition between energy mobilization, cellular recycling, and recovery.
This review evaluates the mechanistic target of rapamycin complex 1 (mTORC1) as a dynamic control point that may link mitochondrial signaling, immunometabolism, inflammation, autophagy, and the post-exertional response. Human data directly related to mTORC1 remain scarce and are based primarily on the phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) in lymphoblasts and on the increase in Ragulator complex proteins in peripheral blood mononuclear cells.
Metabolomic, bioenergetic, immune, neurovascular, intestinal, and autophagic observations also provide functional convergence, although they do not constitute direct evidence of mTORC1 hyperactivation. Analysis of the literature data points to context-dependent mitochondrial dysfunction: the mitochondrial apparatus may appear relatively intact at rest, whereas substrate utilization, respiratory reserve, quality control, and the return to homeostasis become insufficient under stress. Thus, mTORC1 could act as a transition switch when energy stress is expected to promote autophagy, mitophagy, and recovery.
The exploratory signal obtained with rapamycin reinforces the value of mechanistic intervention, pending therapeutic validation. This hypothesis must be tested through longitudinal studies following standardized stimulation, with coordinated measurements of mTORC1 signaling, the AMP-activated protein kinase (AMPK)–Unc-51-like kinase 1 (ULK1) axis, autophagic flux, and respiratory reserve for up to 48 h.
A better understanding of the pathophysiology of PEM in ME/CFS could lead to therapeutic advances in this common and debilitating condition for which no specific treatment is currently available. mTORC1 may act as a transition switch when energy stress should promote autophagy, mitophagy, and recovery.
Web | DOI | Journal of Translational Medicine