Akiko Iwasaki, an immunobiologist at Yale School of Medicine who was not involved in the work, praises the research as “very well done” but cautions that the suspect protein is likely “a piece of the puzzle, as opposed to explaining the whole disease.” The findings suggest it could act as one of several “middlemen” between whatever sparks the illness and symptoms such as fatigue, she says.
Paul Hwang, a physician-scientist at the National Heart, Lung, and Blood Institute (NHLBI), and his colleagues initially set out to study a 38-year-old woman with a cancer-promoting mutation in a gene called TP53. Unlike her brother and her father, who shared this mutation, the woman (referred to as S1 in the study) was experiencing extreme long-term fatigue, though she hadn’t received a formal ME/CFS diagnosis.
Hwang’s team examined tissue samples from her muscle, looking for abnormalities in biochemical pathways related to TP53. That search revealed high levels of a protein called WASF3. It’s known to play a role in a cell’s ability to move, Hwang says, but the team found a little-cited 2011 study of gene activity in ME/CFS patients that predicted it might contribute to that condition, too.
The NHLBI researchers wondered whether WASF3 was interacting with mitochondria, cellular compartments responsible for energy generation that have been suggested to malfunction in people with ME/CFS and Long Covid. Sure enough, by changing levels of WASF3 inside cultured cells from S1 as well as in other human and mouse cells, the team found the protein could disrupt mitochondrial function. Specifically, high levels of WASF3 interfered with the assembly of mitochondrial proteins into molecular complexes that support normal energy production.
Hwang’s group next genetically engineered mice to produce elevated amounts of WASF3. These animals also had defects in their mitochondrial function and were only able to run about half as far on a treadmill as regular mice.
Curious as to whether these results might be relevant to people formally diagnosed with ME/CFS, the researchers compared muscle samples from 14 people living with the illness with those of 10 healthy individuals. They found higher average levels of WASF3—and lower levels of the associated mitochondrial protein complexes—in people with the condition.
“It’s extremely encouraging” to see this kind of detailed molecular approach applied to an understudied illness like ME/CFS, says Mady Hornig, a physician-scientist studying the condition at the Columbia University Mailman School of Public Health. Although the NHLBI researchers didn’t study Long Covid directly, their findings “stand to address a very common set of health issues that are very tightly tied to disability in [both] Long Covid and ME/CFS,” she says.
Hornig, who has had Long Covid since 2020, adds that further work could try to address whether WASF3 also affects brain function. Deficits in brain energy metabolism may explain the cognitive fatigue that many ME/CFS patients find most debilitating, she says.
It’s not clear what causes high WASF3 levels in the first place. Hwang suggests a role for endoplasmic reticulum (ER) stress—a dysfunction of membranes that help the cell fold up its proteins. Viruses can trigger ER stress, perhaps explaining why ME/CFS and related conditions often arise after infection. (S1 told Hwang her fatigue started after she caught mononucleosis as a teenager.)
Several of the lab’s experiments support Hwang’s proposal: Both S1 and the people with ME/CFS had biochemical signatures of ER stress in their muscles, and treating S1’s cells in a dish with a drug that blocks ER stress lowered WASF3 levels and restored mitochondrial function. On the flipside, using toxins to artificially induce ER stress in cultured cells or in mice caused a rise in WASF3 levels, Hwang says.
But more work is needed to understand this link, says Pere Puigserver, a cell biologist at Harvard Medical School. ER stress can itself be prompted by mitochondrial dysfunction, making it hard to pin down the order of events leading to fatigue, he says. WASF3’s multiple cellular roles mean it might have other effects in people with ME/CFS, too, he adds.
Hwang acknowledges there are likely to be other pathways causing fatigue in ME/CFS and Long Covid, and that the drivers of illness might be different for different people. His group is now looking at drugs that could put the brakes on ER stress or reduce WASF3’s effects on mitochondria, with an eye toward designing a clinical study.
ME/CFS (kbin)
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