Wang et al. (2023)
- Authors: Ping-yuan Wang, Jin Ma, Young-Chae Kim, Annie Y. Son, Abu Mohammad Syed, Chengyu Liu, Mateus P. Mori, Rebecca D. Huffstutler, JoEllyn L. Stolinski, S. Lalith Talagala, Ju-Gyeong Kang, Brian T. Walitt, Avindra Nath, Paul M. Hwang
- Institutes: Cardiovascular Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, NIH MRI Research Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, Clinical Neurosciences Program, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD
- Publisher: Proceedings of the National Academy of Sciences (PNAS)
- Link: DOI
Summary
This study identifies WASF3 as a molecular link between endoplasmic reticulum stress and the debilitating fatigue seen in ME/CFS. By demonstrating how this protein physically blocks energy production in muscles, the research opens a new avenue for diagnostic markers and targeted treatments. These findings may also have significant implications for understanding related conditions, such as Long COVID and rheumatic diseases.
What was researched?
The study investigated how the protein WASF3 affects mitochondrial energy production and whether its dysregulation contributes to exercise intolerance in ME/CFS.
Why was it researched?
While ME/CFS patients suffer from severe energy depletion, the underlying molecular mechanism for this bioenergetic deficiency has remained largely unknown. Researchers sought to identify specific molecules that impair muscle metabolism under conditions of cellular stress.
How was it researched?
Researchers performed a detailed clinical investigation of a patient with chronic fatigue, generated transgenic mice overexpressing WASF3, and analyzed skeletal muscle biopsies from a cohort of ME/CFS patients. They utilized advanced imaging, exercise testing, and molecular assays to track how WASF3 interacts with mitochondrial complexes and how ER stress inhibitors like Salubrinal 💊 and Tauroursodeoxycholic acid (TUDCA) 💊 affect this process.
What has been found?
The study found that WASF3 levels are elevated in the muscle of ME/CFS patients due to endoplasmic reticulum stress. This excess WASF3 physically interferes with the assembly of mitochondrial ‘supercomplexes,’ specifically preventing Complex III and Complex IV from working together efficiently. In mice, high WASF3 levels led to a 50% reduction in running capacity and increased lactic acid. Reducing ER stress in patient cells successfully lowered WASF3 levels and restored normal mitochondrial respiration.
Discussion
The findings suggest that ‘ER stress response failure’ is a key driver of mitochondrial dysfunction in ME/CFS. While the initial discovery involved a patient with a specific genetic mutation, the confirmation in a broader ME/CFS cohort suggests a more universal mechanism. Future research must determine what triggers the initial ER stress in these patients.
Conclusion & Future Work
WASF3 is a critical mediator of exercise intolerance that could serve as a drug target. Modulating ER stress pathways offers a promising therapeutic strategy to improve bioenergetics in patients with ME/CFS and potentially Long COVID.