Review Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2025, Syed, Karius, Wang, Hwang

Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Abu Mohammad Syed; Alexander K. Karius; Jin Ma; Ping-yuan Wang; Paul M. Hwang

ME/CFS is a debilitating multisystem disorder of unclear etiology that affects many individuals worldwide. One of its hallmark symptoms is prolonged fatigue following exertion, a feature also observed in long COVID, suggesting an underlying dysfunction in energy production in both conditions. Here, mitochondrial dysfunction and its potential pathogenetic role in these disorders are reviewed.

Link | PDF (Physiology) [Paywall]

 

Many will recall Paul Hwang was the NIH researcher behind the WASF3 study
https://www.s4me.info/threads/wasf3...onic-fatigue-syndrome-2023-hwang-et-al.34776/

 

Spoiler: Experimenting with on-device Apple Intelligence summary

ME/CFS Prevalence: Affects ~1% of the general population in the United States, with women being affected at a rate 3 times higher than men.

ME/CFS Impact: Causes significant disability worldwide, impacting patients, family members, and society through healthcare costs and loss of productivity.

ME/CFS Research Challenges: Lack of specific diagnostic tests and targeted therapies limit effective management, and the growing number of long COVID cases highlights the urgency of advancing research.

ME/CFS Complexity: ME/CFS is a complex condition influenced by cellular dysfunction, genetic predisposition, and environmental factors, leading to diverse and unpredictable symptoms.

Mitochondrial Dysfunction: Mitochondrial dysfunction, potentially contributing to fatigue and post-exertional malaise, is a key area of research in understanding ME/CFS.

Therapeutic Potential: Understanding mitochondrial dysfunction in ME/CFS may lead to new therapeutic targets and treatments.

Mitochondrial Dysfunction in ME/CFS: Mitochondrial dysfunction is a potential contributor to the symptoms of ME/CFS, including fatigue, cognitive impairment, and immune system abnormalities.

Mechanism of Mitochondrial Dysfunction: The exact mechanism of mitochondrial dysfunction in ME/CFS is unclear, but it may be a cause or effect of the underlying pathogenesis.

Importance of Mitochondrial Function: Mitochondria play a crucial role in cellular energy production and overall cellular homeostasis, and their dysfunction can contribute to various diseases.

Mitochondrial Dysfunction in ME/CFS: Patients with ME/CFS exhibit mitochondrial dysfunction, characterised by reduced ATP synthesis, increased glycolytic activity, and decreased oxygen extraction during exercise.

Metabolic Profiling in ME/CFS: Metabolic profiling of blood samples from ME/CFS patients reveals specific differences compared to healthy subjects, suggesting potential metabolic perturbations.

Brain MRS Findings in ME/CFS: Brain MRS studies have shown elevated lactate levels in ME/CFS patients, potentially linked to neuroinflammation and mitochondrial dysfunction.

Mitochondrial Dysfunction in ME/CFS: Despite abnormalities in mitochondrial function, ME/CFS is not classified as a mitochondrial disease due to the lack of specific genetic changes.

Mitochondrial DNA and ME/CFS: Studies have not found significant associations between mitochondrial DNA variations and ME/CFS, but certain mtDNA haplogroups and SNPs are linked to specific symptoms.

Oxidative Stress in ME/CFS: ME/CFS patients exhibit increased oxidative stress, characterised by elevated levels of oxidative markers and reduced antioxidant levels.

CoQ10 Function: CoQ10 is an antioxidant that protects cells from oxidative stress and is involved in ATP production.

Mitochondrial Dysfunction: Mitochondrial dysfunction can lead to increased ROS production, potentially contributing to oxidative stress and cellular dysfunction in ME/CFS.

Peroxisomal Dysfunction: Peroxisomal dysfunction, suggested by plasma metabolomic profiling in ME/CFS patients, may further contribute to oxidative stress and cellular dysfunction.

WASF3 Overexpression: Overexpression of WASF3 protein is linked to decreased mitochondrial respiration and disrupted mitochondrial respiratory supercomplexes.

Mechanism of Action: WASF3 interacts with CIII and destabilises CIV subunits, leading to mitochondrial dysfunction.

ME/CFS Association: Elevated WASF3 levels and ER stress markers are observed in skeletal muscle biopsies of ME/CFS patients.

ER Stress and Mitochondrial Dysfunction: ER stress, potentially triggered by viral infections, disrupts mitochondrial function and contributes to oxidative stress.

WASF3 as a Potential Mediator: Increased WASF3 levels, observed in ME/CFS, could be part of an immune response to perceived stimuli, potentially linking ER stress to mitochondrial dysfunction.

Impact on ME/CFS Symptoms: Impaired mitochondrial function in ME/CFS may explain exercise intolerance and slow recovery from fatigue due to ATP depletion, slow oxidative metabolism, and increased oxidative stress.

Mitochondrial Dysfunction Impact: Extends beyond energy insufficiency, potentially affecting brain function and contributing to neurocognitive symptoms.

Immune System Dysregulation: Altered immunoglobulin, cytokine, and cellular component profiles, along with evidence of chronic inflammation and gut microbiome changes, suggest immune system dysregulation.

Mitochondrial Role in Immune Cells: Mitochondria are crucial for immune cell function, particularly T cells, which undergo metabolic reprogramming to respond to pathogens.

WASF3 Function: Regulates actin cytoskeleton, essential for T cell and B cell receptor signalling, and potentially involved in immune metabolism and function.

WASF3 Structure: Contains a N-terminal WHD and a C-terminal VCA region, which binds actin and Arp2/3 for regulating actin polymerization.

WASF3 Metabolic Impact: May reprogram cell metabolism by suppressing mitochondrial oxidative phosphorylation and enhancing glycolysis.

WASF3 and Neuroinflammation: WASF3, highly expressed in the brain, may be involved in neuroinflammation, a key feature of ME/CFS.

WASF3 and Immune Response: Elevated WASF3 levels activate p38 MAPK, a key cellular stress mediator, potentially as a feedback signal to promote mitochondrial biogenesis.

WASF3 and Long COVID: Investigating the role of WASF3 in immune cells could provide insights into the chronic inflammatory characteristics observed in Long COVID patients.

Fatigue Syndromes and Viral Infections: COVID-19, like ME/CFS, often follows an infection, with EBV being a common trigger for ME/CFS.

Long COVID and ME/CFS Symptoms: Up to 20% of COVID-19 patients experience lingering fatigue, cognitive impairment, and other symptoms resembling ME/CFS.

Mitochondrial Dysfunction in Fatigue: Emerging research suggests mitochondrial dysfunction as a common factor in both ME/CFS and long COVID, potentially contributing to fatigue and exercise intolerance.

Mitochondrial Dysfunction Treatment: Therapeutic approaches to correct mitochondrial dysfunction could provide symptomatic relief in ME/CFS patients.

Treatment Approaches: Mitochondrial biogenesis enhancers, metabolic modulators, and antioxidant supplements have been explored to enhance mitochondrial function and improve symptoms in ME/CFS patients.

Cofactor Supplementation: Coenzyme Q10 (CoQ10) and NADH, essential cofactors for mitochondrial function, have been tested as supplements to improve symptoms in ME/CFS patients.

Mitochondrial Dysfunction in ME/CFS: Mitochondrial dysfunction is a key factor in ME/CFS, with studies exploring treatments targeting mitochondrial function.

Treatment Trials: Various treatments, including D-Ribose, KPAX002, sodium dichloroacetate (DCA), red ginseng (HRG80), and quercetin, have shown some benefits in improving symptoms.

Limitations and Future Directions: Despite some positive results, these treatments have not significantly impacted ME/CFS management due to modest benefits and variable efficacy.

Mitochondrial Dysfunction: Recurring theme in ME/CFS pathophysiology, potentially contributing to multi-system symptoms.

Clinical Heterogeneity: Challenges in diagnosis and treatment due to varying symptoms and lack of specific biomarkers.

Therapeutic Potential: Salubrinal, a PP1 inhibitor, shows promise in reducing ER stress and restoring mitochondrial function, but challenges remain.

WASF3 as a Potential Mediator: Recent study suggests WASF3 might be involved in mitochondrial dysfunction in ME/CFS, linking to cellular energy, ER stress, and immunity.

Oxidative Stress and ER Stress: Oxidative stress and redox imbalance can trigger ER stress, and its role in ME/CFS, particularly in relation to WASF3, is an area for further investigation.

Targeting WASF3 for Insights: Targeting WASF3 through ER stress modulation could provide insights into the molecular pathways of ME/CFS pathogenesis and serve as a potential biomarker for treatment efficacy.

WASF3's Role in Metabolism: WASF3 may regulate metabolism by disrupting mitochondrial respiration and promoting glycolysis.

WASF3's Role in Immunity: WASF3 may support immune system activation by promoting metabolic shifts.

Impact on ME/CFS: Prolonged activation of the WASF3 pathway may contribute to chronic inflammation and energy deficiency in ME/CFS.

 

It's not what I was hoping for when I saw Hwang's name listed as author but this shows that they are still working on WASF3 and making an argument for its relevance!

Hwang never replied to the email I sent him last year so I thought maybe we weren't going to hear any more about this finding.

In the extracts it says Salubrinal shows promise (I assume that would be in vitro or animal model testing), but 'challenges remain'. Intriguing...

I hope they publish some more basic research or even some trial results soon!

 

I agree, that bothered me.

 

I don't think we can conclude that from the article. It's just an invited review.

 

Why would they publish a review nearly 2 years after their finding came out if they'd given up and moved on to other things?

 

Who knows. People publish anything nowadays, primarily because that's what's good for your career.

Possibly they are still working on it, maybe they and others have already failed to replicate the findings or maybe there's a publication coming out soon. Simply replicating the Hwang et al work would be fairly simple and quick work, very cheap and sufficiently many people have access to the necessary samples. For all the chatter one can hear from the NIH, I haven't heard WASF3 being mentioned once.

I don't know how invited reviews work for the AJP, but if it's basically just free citations for you, as it is with some other journals, independently of what they are working on, most researchers would agree to write one.

 

Very good points. Honestly I thought before I got sick it was just humanities academia that was messed up like this. In lit academia people have to teach and publish so much they don't even have time to read the books they need to to advance their research. Terrifying that it's all science too. Not just for us but the wider implications of publish or perish low quality stuff in terms of engineering, public health etc etc.


If it is so simple to replicate WASF3 why hasn't Rob Wust done it? I think we discussed this in the big WASF3 thread and he wasn't able for some reason. It would be so useful to know if it replicates in a larger cohort.

You are right that we don't know. Hopefully we will know more soon. All this uncertainty is so frustrating.

 

I was in touch with Dr. Hwang recently, and his lab is still pursuing the WASF3 research (assuming they weren't part of the NIH massacre). I don't have details, but apparently the basic research is continuing in hopes of justifying an interventional trial as soon as 2026. But of course all that depends on their results, so the wait continues....

 

Thank you for this update.

I’m very worried someone like him risks being part of the NIH massacre.

 

Got my hands on the paper itself. My read is he is not phoning in a cheap review for citations; quite the opposite. He seems consumed by the idea WASF3 could explain everything. Everything!

A relevant excerpt:

Potential clues that WASF3 may be involved in the immune system come from early observations that JAK2/STAT3 pathway can regulate WASF3 through both
transcriptional and protein phosphorylation mechanisms, whereas overexpression of WASF3 alone activates the NFKB pathway (22, 104). In our recent study, we found that ER stress increases WASF3 levels, and the subcellular fraction of WASF3 localized to mitochondria appears to be post-translationally modified by phosphorylation in mouse myoblasts (115).

Because WASF3 is highly expressed in brain tissue (95, 98), it is also tempting to speculate that disruption of WASF3 homeostasis could be involved in
neuroinflammation as observed in ME/CFS.
...
Considering these disparate yet potentially interconnected observations, it could be fruitful to investigate the role of WASF3 in immune cells and explore whether some of the chronic inflammatory characteristics seen in ME/CFS patients can be replicated in WASF3 mouse models.

I get the sense that if there's funding he might go bug-eyed crazy and run a lot of wasf3 experiments. The paper thanks "the Division of Intramural Research of the NHLBI, NIH (HL005101) (to PMH)." I will look and see if that's one that has had its viscera spilled by the Presidential Katana.

 

Here's a graphic that shows Hwang's new wasf3-centric view of the universe!



Figure 1. A model of how WASF3 may play a central role in regulating metabolism and immunity in response to ER stress and other signals.

Upon ER stress, the level of WASF3 protein may rise at the contact sites between the endoplasmic reticulum (ER) and mitochondria. WASF3 disrupts the assembly of
respiratory complexes, inhibiting mitochondrial respiration and oxidative phosphorylation.

In parallel, WASF3 overexpression promotes actin polymerization, which drives glycolysis and further suppresses mitochondrial respiration. This metabolic shift may support immune system activation for host defense. However, prolonged activation of this pathway can lead to chronic inflammation and energy deficiency, contributing to the symptoms of ME/CFS.

 

Is there a way to read behind the paywall...?