mTORC1 may act as a transition switch in ME/CFS post-exertional malaise

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a common, debilitating multisystemic disease whose cardinal symptom is post-exertional malaise (PEM), a delayed and sustained worsening of symptoms after physical, cognitive, emotional, or orthostatic stress. A new review published in the Journal of Translational Medicine argues that 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, and it proposes 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.

The review, authored by Anthony Sunseri, Roger Gaudreault, and Frédérique Retornaz, is explicit about the limits of the current evidence base. Human data directly related to mTORC1 in ME/CFS remain scarce and are based primarily on the phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) in lymphoblasts and on an increase in Ragulator complex proteins in peripheral blood mononuclear cells. Metabolomic, bioenergetic, immune, neurovascular, intestinal, and autophagic observations provide functional convergence, the authors note, although they do not constitute direct evidence of mTORC1 hyperactivation.

A central concept of the review is context-dependent mitochondrial dysfunction. According to the analysis of the literature, 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. On this reading, mTORC1 could act as a transition switch that, when energy stress is expected, should promote autophagy, mitophagy, and recovery. The authors describe an exploratory signal obtained with rapamycin as reinforcing the value of mechanistic intervention, while stressing that therapeutic validation is still pending.

To move the hypothesis forward, the review proposes a concrete research agenda: 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 hours. The authors argue that 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. As a review, the article synthesizes existing observations rather than presenting new experimental results, and its central proposal remains a hypothesis to be tested rather than an established mechanism.

Subject of Research: A mechanistic review of mTORC1 signaling and context-dependent mitochondrial dysfunction in ME/CFS

Article Title: mTORC1 dysregulation and context-dependent mitochondrial dysfunction in ME/CFS: a mechanistic and translational review

Article References: Sunseri, A., Gaudreault, R., & Retornaz, F. (2026). mTORC1 dysregulation and context-dependent mitochondrial dysfunction in ME/CFS: a mechanistic and translational review. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09132-8

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09132-8

Keywords: ME/CFS, mTORC1, mitochondrial dysfunction, post-exertional malaise, autophagy, mitophagy, AMPK, ULK1, rapamycin, Journal of Translational Medicine, review, dysregulation