WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome.
Wang, Ping-Yuan, Ma, Jin, Kim, Young-Chae et al. · Proceedings of the National Academy of Sciences of the United States of America · 2023 · DOI
Quick Summary
Researchers found that a protein called WASF3 may be responsible for exercise intolerance in ME/CFS by interfering with how mitochondria (the energy-producing parts of cells) work in muscles. When WASF3 levels were high, both mice and cells from ME/CFS patients showed reduced energy production capacity. Lowering WASF3 in the patient's cells improved their mitochondrial function, suggesting this protein could be a potential treatment target.
Why It Matters
This study identifies a specific molecular mechanism that could explain the energy deficiency underlying exercise intolerance in ME/CFS, potentially opening new avenues for targeted treatment. The findings suggest that therapies targeting WASF3 or ER stress may help restore mitochondrial function and improve symptoms in ME/CFS and related fatigue conditions.
Observed Findings
WASF3 protein levels were elevated in skeletal muscle biopsies from ME/CFS patients compared to controls
Increased WASF3 expression impaired mitochondrial respiratory supercomplex assembly and reduced Complex IV levels in skeletal muscle
ER stress induction by endotoxin increased WASF3 levels and decreased Complex IV in mouse muscle
Pharmacologic inhibition of ER stress in patient-derived cells reduced WASF3 levels and improved mitochondrial respiratory function
Inferred Conclusions
WASF3 overexpression disrupts mitochondrial respiratory supercomplex formation, contributing to bioenergetic deficiency and exercise intolerance
ER stress activation may drive WASF3 upregulation as a mechanism linking systemic stress to mitochondrial dysfunction in ME/CFS
Targeting WASF3 or upstream ER stress pathways may represent a viable therapeutic approach to restore mitochondrial function
This mechanism may also underlie fatigue in related conditions such as long COVID and rheumatic diseases
Remaining Questions
Is WASF3 elevation present across all ME/CFS patients or only a subset, and does it correlate with disease severity or specific symptom profiles?
What This Study Does Not Prove
This study does not prove that WASF3 elevation is the sole or primary cause of ME/CFS in all patients, as it may represent one pathway among many. The work is primarily mechanistic and correlative; whether WASF3 reduction would clinically improve exercise intolerance in ME/CFS patients requires controlled clinical trials. The findings may not be generalizable to all ME/CFS presentations, given the heterogeneity of the disease.