Baffling perhaps to medical doctors who have long dismissed ME/CFS, but not so much to researchers who have steadily been building a picture of what triggers this debilitating illness, nor to those who live with its unrelenting exhaustion every day.
Inside every cell are energy-making machines, the mitochondria, which power our cells, replenish our brains, and keep our muscles moving.
Now a new study from a team of US researchers adds evidence to a growing theory that malfunctioning mitochondria might be one potential cause of energy-limiting illnesses such as ME/CFS and long COVID.
People living with ME/CFS often describe feeling utterly depleted or sapped of energy like a dead battery. Unlike every day tiredness, chronic fatigue syndrome doesn't ease with sleep, and often it gets worse with exercise, not better.
Investigating one case of chronic fatigue, Paul Hwang, a physician-scientist at the US National Heart, Lung, and Blood Institute, and colleagues stumbled upon a forgotten protein found at oddly high levels in the woman's cells.
Viruses and inflammation can damage mitochondria, two possible ways of creating energy production problems that deplete cells of fuel. But exact mechanisms of how mitochondria crumble remain unclear.
The suspect protein in this case, called WASF3, had been linked to chronic fatigue syndrome before, in a 2011 meta-analysis that no one had followed up on. A study of the woman's blood supported suspicions that symptoms of extreme fatigue were linked with an overexpression of the protein.
In experiments with cultured cells, Hwang and colleagues found that WASF3 disrupted mitochondrial function by interfering with protein complexes that usually unite to support energy production. The cells' mitochondria used less oxygen and produced less energy.
Mice engineered to overexpress WASF3 also had dysfunctional mitochondria, and their muscles fatigued quickly on exercise tests too.
This echoed the results of tests on the 38-year-old woman's muscles, which revealed her mitochondria were abnormally slow to replenish energy stores after brief exercise.
And when Hwang and colleagues went looking for WASF3 in muscle samples of 14 people with ME/CFS, they found its levels elevated again. Compared to 10 healthy controls, people with ME/CFS also had lower levels of the mitochondrial protein complexes in their muscle cells.
"Our study provides a molecular explanation for the patient's bioenergetic deficiency, which may be applicable to not only ME/CFS but also other conditions that feature chronic fatigue such as long COVID," Huang and colleagues write in their published paper.
As for how WASF3 becomes elevated, the researchers have a few ideas from their study. They think too much WASF3 protein might be the result of stress on the mitochondria's close companion, the endoplasmic reticulum.
The endoplasmic reticulum (ER) is responsible for folding and packaging proteins, and viral infections have been reported to trigger ER stress responses.
Muscle biopsy samples from the cohort of people with ME/CFS had biochemical markers of ER stress, and so did the woman's cells.
Inducing ER stress in mice sent WASF3 levels rising, while treating cells with a drug that inhibits ER stress lowered WASF3 levels – and importantly, restored mitochondrial function.
While more research is needed to confirm these links, the study is an encouraging step towards pinning down the underlying causes of ME/CFS, and designing therapies to treat it.
For too long this devastating illness has been overlooked, so all of those research avenues are worth pursuing until we understand more.
The study has been published in PNAS.