#WASF3

[ruthfeiertag]

https://www.washingtonpost.com/health/2023/09/17/fatigue-cfs-longcovid-mitochondria/

Here’s an article about Amanda Twinam’s search for answers to her problems with fatigue, a search that someday may lead to a fuller understanding of ME/CFS, similar diseases, and to treatments. For many of us, these ameliorations or cures will come too late for us to recover our health or for us to recover any semblance of the lives we should have had, but perhaps it will give all the young(er) people with ME, Long-Covid, etc., hope.

[anumberofhobbies]

I wonder what the status of this from last year is now?

To see if WASF3 dysfunction might be involved in ME/CFS, the team compared muscle tissue samples taken from 14 people with ME/CFS to samples from 10 healthy volunteers. They found substantially higher levels of WASF3 in most of the people with ME/CFS. This dysfunctional increase in WASF3 seemed to be linked to impairment of a cellular signaling pathway called the ER stress pathway. When the team treated human muscle cells with a compound known to increase ER stress, they saw a corresponding harmful increase in WASF3. The researchers treated cells from the initial study participant with an experimental drug, called salubrinal, known to reduce ER stress. After this treatment, WASF3 levels decreased in the cells, more mitochondrial energy complexes formed, and energy production improved. “We hope to embark on clinical studies to investigate whether this type of strategy can also work in patients to improve energy levels,” Hwang says. Mitochondrial dysfunction has been found in some people with Long COVID and other conditions that include fatigue. More research is needed to understand whether targeting ER stress may also be a promising approach for these conditions.

[pandemic-info]

A protein that disrupts cells’ energy centers may be a culprit in chronic fatigue syndrome | Science | AAAS

New study offers clues as to how exhaustion could arise in people with ME/CFS—and potentially related conditions such as Long Covid

People living with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) struggle not only with extreme exhaustion and the cognitive problems known as brain fog, but with a profound lack of information about what causes their symptoms and how to treat them. Scientists have yet to pin down the biology underlying the condition, which affects up to 2.5 million people in the United States alone, according to some estimates.

Now, researchers have identified a protein that’s present at unusually high levels in the muscles of people with ME/CFS and that disrupts cells’ ability to generate energy. The findings, reported today in the Proceedings of the National Academy of Sciences, could point to new therapeutics for this condition and for illnesses that share similar characteristics, such as Long Covid.

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.

...

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.

[longhaulerbear]

The authors were excited enough about the WASF3 finding to dig deeper and ultimately add substantial insights into the role WASF3 plays in the mitochondria. Its ability to disrupt the mitochondrial enzyme supercomplexes in ME/CFS was notable because genetic conditions that inhibit these supercomplexes are characterized by, you guessed it, exercise intolerance. The authors even proposed that high WASF3 levels in the brain may be contributing to mitochondrial problems and brain fog in ME/CFS.

This saga – which came together because of an (undiagnosed) ME/CFS patient in a cancer study and an obscure paper that came out of a novel and exploratory effort 15 years ago – demonstrates how serendipity can strike in the medical world.

Akiko Iwasaki, an immunobiologist at Yale School of Medicine told Science that the study was “very well done”. She cautioned that the suspect protein is likely “a piece of the puzzle, as opposed to explaining the whole disease” and could act as one of several “middlemen” between whatever sparks the illness and symptoms such as fatigue.

She’s probably right given the many other indications (disrupted autophagy, reduced fatty acid metabolism, high levels of intracellular calcium, complex V dysregulation, HHV-6 reactivation/mitochondrial fragmentation, citrate synthase deficiency, inborn errors of metabolism) that the mitochondria are involved in ME/CFS. What we really need is a full-court press on the mitochondria.

[cancersfakianakis1]

Promotion of Invasion by Mutant RAS is Dependent on Activation of the WASF3 Metastasis Promoter Gene

Abstract

Metastasis represents an end stage in the evolution of cancer progression and has been related to specific genetic pathways. Overexpression of mutant RAS in particular appears to promote invasion and metastasis, although exactly how this occurs has not been well characterized. We have previously shown that activation of the WASF3 protein regulates actin cytoskeleton dynamics that promote invasion. In this report we investigated how WASF3 overexpression interacts with mutant RAS to increased invasion and metastasis. The ability of RAS to promote invasion and metastasis was shown to be dependent on WASF3 activation in a PI3K and AKT dependent manner. Proteomics analysis demonstrates the presence of AKT in the WASF3 immunocomplex which is enhanced by overexpression of mutant RAS. During these processes activation of ERK1/2 is not affected by loss of WASF3 expression. Analysis of the relative involvement of p85 and p110 in the WASF3 complex demonstrates that mutant RAS promotes dissociation of p85 promoting activation of p110. These studies provide a deeper understanding of the critical role for WASF3 in facilitating increased invasion potential in cancer cells expressing mutant RAS and supports the idea that targeting WASF3 in metastatic cells overexpressing RAS may be used to suppress invasion and metastasis. This article is protected by copyright. All rights reserved.

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