WASF3 – disrupting cellular energy production in ME/CFS


Malfunctioning mitochondria have long been thought to play a role in ME/CFS but working out exactly what is wrong is taking time.

You may hear mitochondria called “the powerhouse of the cell.” Mitochondria are an energy factory. The job of mitochondria is to process oxygen and convert substances from the foods you eat into energy. Mitochondria exist in nearly every cell in the human body. Mitochondria produce 90% of the energy our bodies need to function. [Cleveland]

US researchers have now discovered unusually high levels of a protein called WASF3 in a woman with ME/CFS.  They tested it in cultured cells and mice and found the protein could disrupt mitochondrial function. They then compared healthy people with people with ME/CFS and found all people with ME/CFS had high protein levels.

Other experts warn this might only be part of the answer but the group is now looking at drugs that could reduce WASF3’s effects on mitochondria, with an eye toward designing a clinical study.


WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome by Ping-yuan Wang, Jin Ma, Young-Chae Kim and Paul M Hwang in PNAS Vol. 120, No. 34, Aug 2023 [doi.org/10.25444/nhlbi.23681013]


Chronic fatigue is a debilitating symptom that affects many individuals, but its mechanism remains poorly understood. This study shows that endoplamic reticulum (ER) stress–induced WASF3 protein localizes to mitochondria and disrupts respiratory supercomplex assembly, leading to decreased oxygen consumption and exercise endurance.

Alleviating ER stress decreases WASF3 and restores mitochondrial function, indicating that WASF3 can impair skeletal muscle bioenergetics and may be targetable for treating fatigue symptoms.

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and is diagnosed in the absence of a specific cause, making its clinical management challenging.

A better understanding of the molecular mechanism underlying this apparent bioenergetic deficiency state may reveal insights for developing targeted treatment strategies.

We report that overexpression of Wiskott-Aldrich Syndrome Protein Family Member 3 (WASF3), here identified in a 38-y-old woman suffering from long-standing fatigue and exercise intolerance, can disrupt mitochondrial respiratory supercomplex formation and is associated with endoplasmic reticulum (ER) stress.

Increased expression of WASF3 in transgenic mice markedly decreased their treadmill running capacity with concomitantly impaired respiratory supercomplex assembly and reduced complex IV levels in skeletal muscle mitochondria. WASF3 induction by ER stress using endotoxin, well known to be associated with fatigue in humans, also decreased skeletal muscle complex IV levels in mice, while decreasing WASF3 levels by pharmacologic inhibition of ER stress improved mitochondrial function in the cells of the patient with chronic fatigue.

Expanding on our findings, skeletal muscle biopsy samples obtained from a cohort of patients with ME/CFS showed increased WASF3 protein levels and aberrant ER stress activation.

In addition to revealing a potential mechanism for the bioenergetic deficiency in ME/CFS, our study may also provide insights into other disorders associated with fatigue such as rheumatic diseases and long COVID.

Independent: A woman who survived breast cancer twice may have inadvertently furthered long Covid research

Read the story of how Amanda Twinam’s search for answers to her low energy inspired Dr Paul Hwang to study how the protein called WASF3 was plugging up her energy production process. Dr Hwang is now focused on curing ME/CFS, and his team plan to trial a new drug.

Science.org: A protein that disrupts cells’ energy centers may be a culprit in chronic fatigue syndrome

Psychiatrist: A Protein That Zaps Cellular Energy May Underlie Chronic Fatigue

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