WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome, 2023 Hwang et al

AuroraNY said:
If anyone is going to be at the NIH Research Festival in September, there is apparently going to be a poster entitled "Chronic Fatigue Syndrome-associated gene WASF3 mediates immune abnormalities in mouse models."

The presenter is Ananya Ganguly, a visiting postdoctoral fellow in immunology, and the authors are Paul Hwang and others from the original WASF3 paper.


https://researchfestival.nih.gov/2026/posters-session
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That's really interesting. It's been a while since their first MECFS paper. Although Iirc someone said recently they were aware of a failed WASF3 replication attempt ?
 
I have not been on campus for about 15 years, but I seem to remember they had security protocols. Maybe I am misremembering, though. It may be worth a quick phone call - if only to be on the safe side.

And, yes, I'd like to know about what insights the poster has to offer, too.
 
We didn't specifically try to replicate this study but when we have done basic respirometry experiments on fibroblast lines with mitochondrial inhibitors and standard media we haven't seen differences as far as I am aware. I still hold this study as one of the few if only positive results and well conducted studies in this area but I personally moved on from this avenue of investigation (mitochondrial respiration as a primary driver) years ago

there is a bit of buzz around using different substrates or compounds which affect processes upstream of OXPHOS (upstream in terms of energy metabolism) which I think might be more interesting. especially relating to glutamine or lipid catabolism bc those tend to have broader signalling implications that have not been looked at as much
 
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DMissa said:
We didn't specifically try to replicate this study but when we have done basic respirometry experiments on fibroblast lines with mitochondrial inhibitors and standard media we haven't seen differences as far as I am aware. I still hold this study as one of the few if only positive results and well conducted studies in this area but I personally moved on from this avenue of investigation (mitochondrial respiration as a primary driver) years ago

there is a bit of buzz around using different substrates or compounds which affect processes upstream of OXPHOS (upstream in terms of energy metabolism) which I think might be more interesting. especially relating to glutamine or lipid catabolism bc those tend to have broader signalling implications that have not been looked at as much
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Many thanks for the clarification! Yes, it sounded strange, as until now this appears to be the only positive ME/CFS study conducted properly, and a failed replication attempt would likely already be known.

Let’s see what the results of his planned 2027 trial using an FDA-approved repurposed drug targeting ER stress will show.

Very Intriguing case beside F&M Dara and SequenceME!
 
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Lisan_Al_Ghaib_87 said:
Many thanks for the clarification! Yes, it sounded strange, as until now this appears to be the only positive ME/CFS study conducted properly, and a failed replication attempt would likely already be known.

Let’s see what the results of his planned 2027 trial using an FDA-approved repurposed drug targeting ER stress will show.

Very Intriguing case beside F&M Dara and SequenceME!
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Which drug is going to trialed for repurposing for ER stress.
 
V.R.T. said:
If WASF3 was involved in causing symptoms in MECFS, wouldn't it have come up in DecodeME?
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Even though thats very scientifical question which I cannot answer it, doing a fast research on the internet seems that WASF3 is primarily expressed and active in the nervous system under normal physiological conditions thus maybe there is still a conection with the relevant locki indendified in their study.

Input from the "genetics A-Team department" of the forum will be very much appreciated.
 
Lisan_Al_Ghaib_87 said:
Many thanks for the clarification! Yes, it sounded strange, as until now this appears to be the only positive ME/CFS study conducted properly, and a failed replication attempt would likely already be known.

Let’s see what the results of his planned 2027 trial using an FDA-approved repurposed drug targeting ER stress will show.

Very Intriguing case beside F&M Dara and SequenceME!
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If you are looking for a currently available remedy for ER stress, @mariovitali has some information about TUDCA being helpful on twitter

 
www.healthrising.org

WASF3: A Critically Important Process in ME/CFS? Paul Hwang's Surprising Saga - Health Rising

A mitochondrial disrupter called WASF3 could be dysregulating many systems in ME/CFS.
www.healthrising.org

WASF3: A Critically Important Process in ME/CFS? Paul Hwang’s Surprising Saga​

by Cort Johnson | Sep 12, 2026​

THE GIST​

  • Health Rising recently covered two NIH-funded studies suggesting that brain energy levels are low. This blog digs deeper into one of the more intriguing findings of the past couple of years. Paul Hwang’s WASF3 finding could be affecting many areas of the body, including the brain.
  • In fact, Hwang and company believe they may have uncovered a “critically important cellular process” which could be affecting many systems in this disease.
  • Hwang, MD, PhD, is different from most researchers we know. Because he runs his own intramural lab at the NIH, he can quickly act on findings and explore them deeply, and that’s what he’s done with ME/CFS.
  • Hwang’s 2023 ME/CFS paper was astonishing in several ways. For one, he had never published or indicated any interest in ME/CFS. For another, he ran a lab in a part of the NIH (NHLI), which rarely supported ME/CFS. Finally, the study was far more comprehensive – including lab, genetically modified mice, and human studies – than one would have expected from a first-time ME/CFS researcher.
  • It’s even a little crazier than that. Hwang’s whole effort began when he was studying a cancer gene in a family that included a woman whose high WASF3 results surprised him. She just happened to have a long-standing case of ME/CFS.
  • It turns out that WASF3 can disrupt mitochondria by inhibiting part of the electron transport chain. Indeed, Hwang found that knocking down WASF3 levels in her cells improved their mitochondrial functioning. He had just discovered a new way to potentially explain the energy problems in ME/CFS.
  • Further study indicated that this very fatigued woman had multiple mitochondrial abnormalities, and when Hwang knocked down WASF3 levels in her cells, their mitochondrial function improved. When he created transgenic mice with high WASF3 levels in their skeletal muscles, their aerobic function and endurance declined. When he tested ME/CFS patients’ cells, he got similar results.
  • Hwang then turned his attention to the endoplasmic reticulum (ER), which is responsible for folding proteins into their proper shape. He found a dramatic reduction in an ER protein that regulates WASF3. Plus, high levels of a marker of endoplasmic reticulum (ER) stress were found.
  • Interestingly, the endoplasmic reticulum (ER) plays an important role in cellular viral defense. Viruses attempt to counteract this by upregulating genes that impair the ER’s ability to properly fold proteins or remove misfolded ones. High WASF3 levels could therefore result from infection.
  • The authors concluded that “WASF3, induced by ER stress…(provides) a molecular explanation for the energy deficiency symptoms of exercise intolerance and postexertional malaise in a patient with chronic fatigue.”
  • They weren’t nearly done yet, though. It’s long been conjectured that damaged mitochondria are spewing scads of free radicals (reactive oxygen species) into our cells. Hwang, though, believes that instead of being free-radical engines, mitochondria are actually the cell’s premier antioxidant buffers.
  • In Hwang’s view, damaged mitochondria in ME/CFS patients’ cells aren’t spewing free radicals; they’re simply too weak to mop them up effectively.
  • Here’s where the increased WASF3 levels come in, big time. Increased WASF3 levels disrupt exactly that part of the electron transport chain (complex IV) responsible for clearing reactive oxygen species in mitochondria.
  • Because increased levels of free radicals or reactive oxygen species can then damage the endoplasmic reticulum, a vicious circle may occur. High ER stress (caused by infection) dysregulates WASF3, causing it to inhibit the mitochondria’s ability to clear reactive oxygen species. Their levels rise, resulting in more ER stress, higher WASF3 levels, and so on.
  • What’s more, Hwang and colleagues propose that this system is an adaptive response to an infection. The WASF3 elevation should result in a temporary shift to anaerobic energy production – which is what T-cells use early in an infection to produce their clones.
  • Getting stuck in this state, though, would cause T-cell exhaustion and make T-cells less able to recognize and kill infected cells, which is what we see in ME/CFS and long COVID.
  • There’s another potential twist. The authors propose that during exercise, the weakened mitochondria release a factor called mtDNA into the cell interior (cytosol), which looks like viral DNA to the immune system!
  • The innate immune system goes on the attack, wipes out energy stores, and puts the muscles into a hypometabolic, antiviral‑like state.
  • The brain could be affected as well. WASF3 is found throughout the brain, including several regions that require high energy production. The authors believe it may contribute to neuroinflammation.
  • Note that the authors believe the problem lies more in endoplasmic reticulum stress than in WASF3. A small, recent paper from the Hanson labs, which documented large-scale endoplasmic reticulum stress in ME/CFS, suggested that the Hwang group is on the right track.
  • As far back as 2023, Hwang proposed a clinical trial, and in 2025 Avindra Nath said one was on track, but something appears to have happened. I found no evidence that a clinical trial is underway or in the planning stages. Some changes to drug availability may be responsible.
  • So, has Hwang found the kind of “critically important process” which could impact many systems that we’ve been looking for? It’s possible but also entirely conjectural. Our critical need is for large, multisystemic studies that incorporate the brain, the muscles, and the immune system.
  • Those are the kinds of studies the NIH excels in with other diseases but rarely produces for ME/CFS. Hwang, though, appears to be working in a potentially rich, intercollaborative environment at the NIH. Maybe this array of NIH-funded brain and WASF3 studies will cause it to act differently.
  • Because Hwang is an intramural researcher, it’s hard to tell what he’s working on or who he’s working with. I will try and find out what he’s doing.
 
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