A Protein That Zaps Cellular Energy May Underlie Chronic Fatigue

For individuals dealing with chronic fatigue, even minor physical effort can trigger lasting and overwhelming exhaustion. This perplexing condition, also known as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), affects around 2.5 million Americans. However, the reason why their cells struggle to produce energy has remained somewhat of a puzzle.

Now, researchers from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI)  have uncovered a potential culprit behind the energy crisis triggered by activity. It’s a protein called WASF3. 

Their findings, published in the journal PNAS, suggest that WASF3 might impair the function of cell powerhouses called mitochondria. This discovery sheds light on a possible molecular explanation for the challenges ME/CFS patients face in summoning their strength.

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Of Mice and Woman

The study revolved around a 38-year-old woman who had been grappling with severe fatigue and muscle cramps since the age of 16. Despite thorough medical examinations, no clear explanation was found. 

Through advanced MRI technology, researchers identified that her muscles took an exceptionally long time to recover after exercise, indicating compromised energy production. Further investigations demonstrated that her muscle cells struggled to replenish phosphocreatine, a crucial energy store that depletes during exertion, thus pointing to an energy deficit. Additional analysis revealed reduced activity of complex IV, a vital element of the cellular “power plants” known as mitochondria.

Importantly, the patient’s cells exhibited significantly higher levels of WASF3 compared to those of her healthy sibling. Researchers identified this unusual elevation of WASF3 as a potential contributor to the patient’s cellular energy deficit. The combination of impaired phosphocreatine regeneration and reduced complex IV activity provided valuable insights into the molecular basis of her unexplained fatigue and intolerance to exercise.

To delve deeper into the role of WASF3, the researchers engineered mice to produce excessive amounts of this protein. Mirroring the patient, these mice quickly fatigued during treadmill tests. 

The researchers discovered that WASF3 in the mice’s mitochondria obstructed the assembly of complex III and IV, forming “supercomplexes” that boost energy. Despite differences in WASF3 levels, both mice and humans showed comparable reductions in energy-related components due to WASF3’s presence. This suggests that WASF3 might overly impair the regulation of these supercomplexes.

Impaired Power Production

WASF3 is typically responsible for regulating the cell’s cytoskeleton, the framework giving cells their shape. But the study revealed that WASF3 also plays a role in mitochondria where it interacts with respiratory proteins and disrupts the correct assembly of electron transport chain complexes, the cell’s energy generators. This disruption impairs energy production, depriving the cell of ATP, its primary energy currency.

By interfering with the formation of supercomplexes, elevated levels of WASF3 seem to impede mitochondria’s ability to generate energy through oxidative phosphorylation, a crucial process for cells to produce most of their ATP, resulting in energy-deprived cells. This suggests a molecular explanation for the severe fatigue experienced by individuals with ME/CFS.

In earlier studies, the WASF3 gene emerged as a leading candidate in a comprehensive database analysis of samples from ME/CFS patients. However, Paul Hwang, MD, senior researcher with the NHLBI, told Psychiatrist.com, “… there were no follow up studies on this gene related to ME/CFS that we could find, which caused us to delve further into the potential mechanistic role of WASF3 in ME/CFS.”

Unanswered Questions

This proof-of-concept study implies that strategies targeting WASF3 and cellular stress could potentially alleviate the symptoms of ME/CFS. Hwang cautioned against jumping to conclusions at this stage.

“I think we have to be careful not to get too far ahead of our findings, which is currently limited to examining the levels of WASF3 protein levels in the available skeletal muscle samples of ME/CFS patients compared with healthy volunteers,” he said. “At this point, we can only comment on the potential targeting of WASF3 in ME/CFS.”

Hwang added that it will be important to confirm this correlation between WASF3 levels and ME/CFS in additional patients. He also said it would be interesting to investigate whether the protein has a role in the fatigue symptoms of patients with other exhaustion-related conditions such as long COVID. The COVID-19 virus can endure in tissues and prompt a similar cellular reaction, although Hwang stressed the necessity for more baseline data to make a connection with WASF3.

Despite these uncertainties, identifying a molecular mechanism for reduced exercise tolerance could open up avenues for effectively treating debilitating fatigue. Managing excessive levels of the WASF3 protein might aid cells in restoring their energy production and helping patients regain their ability to meet the demands of daily life.

Hwang noted, “Having identified WASF3 as a direct mediator of energy deficiency in ME/CFS, one question would be whether it can be downregulated in ME/CFS patients, and if so, whether that improves their biochemical energy state and symptoms.”