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

Hutan said:
The first test reported on was phosphorus magnetic resonance spectroscopy (P-MRS) in combination with repeat exercise. They say phosphocreatine is used in exercising skeletal muscle; the length of time it takes to get back to the baseline after exercise is the PCr recovery time. They say that this is a non-invasive measure of mitochondrial ATP synthesis capacity.
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ME/CFS Skeptic said:
The 2004 study is a review of several small studies done in the 1990s. I wonder if the technique is still relevant today and if it would be worth repeating it today with a larger sample size. I would suggest an exercise test that is more focussed on muscle endurance rather than a short burst of intense exercise (like CPET).
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At the Lisbon conference on Apr 4 2024 Dr Inderjit Singh from Yale presented that they are currently devloping a leg exercise test where they can measure PCr in real time using MR spectroscopy and then see how the response differs from healthy controls.
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upload_2024-4-5_8-58-31.png

The blue line is the outline of a leg of a person lying down, thigh to the left, and the red line with arrows is the lower leg shown lifting and lowering for exercise.
 
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I have never stopped thinking about this study and I keep an eye on any new research on UPR.

I recently found this pre-print and contacted the senior author to see if he had any thoughts on me/cfs. Hwang's WASF3 paper found a disregulated pattern in the UPR proteins that you'd usually expect to both be elevated (PERK was up, but XBP1 was down) and I thought perhaps it might cross over with this finding.


[Preprint]. 2024 Dec 5:2024.11.30.626188. doi: 10.1101/2024.11.30.626188.
Dynamic modulation of IRE1α-XBP1 signaling by adenovirus
Yumi Jang, Fred Bunz
Abstract


The abundant production of foreign proteins and nucleic acids during viral infection elicits a variety of stress responses in host cells. Viral proteins that accumulate in the endoplasmic reticulum (ER) can trigger the unfolded protein response (UPR), a coordinated signaling program that culminates in the expression of downstream genes that collectively restore protein homeostasis. The model pathogen adenovirus serotype 5 (HAdV5) activates the UPR via the signaling axis formed by inositol-requiring enzyme type 1 (IRE1α) and the X-box binding protein 1 (XBP1), a transcription factor required for immune function. Recent studies have suggested that IRE1α-XBP1 activity supports adenovirus replication. Here, we show that HAdV5 exerted opposing effects on IRE1α and XBP1. IRE1α was activated in response to HAdV5 but the production of the XBP1 isoform, XBP1s, was post-transcriptionally blocked. The tumor suppressor p53, which is eliminated by HAdV5 after infection, inhibited IRE1α activation. The de-repression of IRE1α following the degradation of p53 conceivably reflects a novel antiviral mechanism, which HAdV5 ultimately evades by suppressing XBP1s. Our findings highlight the defective antiviral defenses in cancer cells and further illustrate the opposing mechanisms used by adenoviruses and their host cells to exert control over the UPR, a critical determinant of cell fate.

The lead author got back to me straight away and said this:

Thanks for the kind words. You bring up a interesting point. In fact, Paul Hwang and I have discussed how our results might fit in with his observations in CFS. No simple answers, but viruses could be a link.
Best,
Fred
 
I was reading the WASF3 paper again and I wondered if PCr recovery time had been measured in ME/CFS before. While the paper points to one paper (Chaudhuri and Behan 2004) that identified delayed PCr recovery in ME/CFS patients, AI identified (and I verified) 3 papers where PCr recovery in CFS patients (Fukuda criteria, no PEM required) was not significantly different from controls.

These three studies all had small sample sizes and did not require PEM. One explanation is that they lacked statistical power as a result and that is why no statistically significant difference was found. The other explanation of course is that PCr recovery time is not different in true ME/CFS patients and the 2004 paper is a statistical error.

This suggests that caution is required and these studies ought to be replicated with a larger cohort of properly diagnosed ME/CFS patients.

See below for a more detailed analysis.





McCully and Natelson (2004) (https://journals.physiology.org/doi/full/10.1152/japplphysiol.00141.2003)

The study examined 19 CFS patients meeting the Fukuda criteria (which does not require PEM) and did not find any statistically significant difference in PCr recovery time (40.6 ± 12.6 s for CFS and 40.1 ± 14.0 s for control subjects)

It could be that the null result was because n=19 and some/all of the patients did not have PEM. The test required them to pedal with high intensity for a short period and "All of the subjects performed the tests without incident". This suggests to me that the patients were very mild or did not have PEM at all.

The paper also found no significant difference in Vmax, but other papers have (e.g. this earlier paper by McCully: https://pubmed.ncbi.nlm.nih.gov/8618560/). Again this suggests the Fukuda patients in this PCr study did not (all) have true ME/CFS.

On the other hand, the paper did have some significant findings relating to blood pressure so perhaps some had true ME/CFS.

Jones et al (2010): https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2009.02160.x

This paper examined 16 CFS patients meeting the Fukuda criteria and likewise found no significant differences in the postexercise recovery rate of PCr (CFS: 32.7 ± 9.0 s, controls: 27.2 ± 7.1 s).


Again, this paper did have some significant findings relating to muscle metabolism. It found that proton efflux was suppressed in CFS patients such that we have slower recovery in pH levels following exercise. This suggests that perhaps the Fukuda patients may have had true ME/CFS.

Wong et al (1992): https://sci-hub.ru/10.1378/chest.102.6.1716

This paper examined 22 CFS patients meeting the Fukuda criteria. Table 3 notes that PCr recovery after 1 min, 2 mins, 5 mins were all not significant. Unlike Jones et al, it diid not find any significant difference in the speed of pH recovery. It did find that acidosis occurred more quickly though.

This paper found that PCr levels reached a minimum much earlier in CFS patients than controls (i.e. they could do less exercise) but once the exercise stopped, their PCr returned to normal levels at the same speed as the controls.
 
I wanted to post a few recent UPR papers I found (recalling that the UPR could be tied into the ER stress Hwang found and that the wasf3 goes from the ER to the mitochondria)

1. This one caught my eye because we seem to hear about extracellular matrix, actin and fibroactin so much these days; I'm always attracted to under-studied bits of the cell that people assume are just structural but could have functional properties that are overlooked.

2024 Aug 8;187(16):4289-4304.e26. doi: 10.1016/j.cell.2024.05.057. Epub 2024 Jun 27.
The extracellular matrix integrates mitochondrial homeostasis
Hanlin Zhang 1 , C Kimberly Tsui 1 , Gilberto Garcia 1 , Larry K Joe 1 , Haolun Wu 1 , Ayane Maruichi 1 , Wudi Fan 1 , Sentibel Pandovski 1 , Peter H Yoon 1 , Brant M Webster 1 , Jenni Durieux 1 , Phillip A Frankino 1 , Ryo Higuchi-Sanabria 1 , Andrew Dillin 2
Affiliations
Abstract
Cellular homeostasis is intricately influenced by stimuli from the microenvironment, including signaling molecules, metabolites, and pathogens. Functioning as a signaling hub within the cell, mitochondria integrate information from various intracellular compartments to regulate cellular signaling and metabolism. Multiple studies have shown that mitochondria may respond to various extracellular signaling events. However, it is less clear how changes in the extracellular matrix (ECM) can impact mitochondrial homeostasis to regulate animal physiology. We find that ECM remodeling alters mitochondrial homeostasis in an evolutionarily conserved manner. Mechanistically, ECM remodeling triggers a TGF-β response to induce mitochondrial fission and the unfolded protein response of the mitochondria (UPRMT). At the organismal level, ECM remodeling promotes defense of animals against pathogens through enhanced mitochondrial stress responses. We postulate that this ECM-mitochondria crosstalk represents an ancient immune pathway, which detects infection- or mechanical-stress-induced ECM damage, thereby initiating adaptive mitochondria-based immune and metabolic responses.

2. This one implicates redox imbalance. There's a million papers saying oxidative stress is rampant in ME/CFS but where does that lead? Here's one idea:


2024 Jun 7;81(1):250. doi: 10.1007/s00018-024-05286-0.
Redox regulation of UPR signalling and mitochondrial ER contact sites
Jose C Casas-Martinez 1 2 , Afshin Samali 2 3 , Brian McDonagh 4 5
Affiliations
Abstract
Mitochondria and the endoplasmic reticulum (ER) have a synergistic relationship and are key regulatory hubs in maintaining cell homeostasis. Communication between these organelles is mediated by mitochondria ER contact sites (MERCS), allowing the exchange of material and information, modulating calcium homeostasis, redox signalling, lipid transfer and the regulation of mitochondrial dynamics. MERCS are dynamic structures that allow cells to respond to changes in the intracellular environment under normal homeostatic conditions, while their assembly/disassembly are affected by pathophysiological conditions such as ageing and disease. Disruption of protein folding in the ER lumen can activate the Unfolded Protein Response (UPR), promoting the remodelling of ER membranes and MERCS formation. The UPR stress receptor kinases PERK and IRE1, are located at or close to MERCS. UPR signalling can be adaptive or maladaptive, depending on whether the disruption in protein folding or ER stress is transient or sustained. Adaptive UPR signalling via MERCS can increase mitochondrial calcium import, metabolism and dynamics, while maladaptive UPR signalling can result in excessive calcium import and activation of apoptotic pathways. Targeting UPR signalling and the assembly of MERCS is an attractive therapeutic approach for a range of age-related conditions such as neurodegeneration and sarcopenia. This review highlights the emerging evidence related to the role of redox mediated UPR activation in orchestrating inter-organelle communication between the ER and mitochondria, and ultimately the determination of cell function and fate.


3. This one talks about how UPR can lead to intracellular communication, which is important if you're interested in things that go beyond just a few cells.

doi: 10.1016/j.canlet.2025.217613. Epub 2025 Mar 5.
Unraveling UPR-mediated intercellular crosstalk: Implications for immunotherapy resistance mechanisms
Si Lu 1 , Qimin Zhou 2 , Rongjie Zhao 3 , Lei Xie 4 , Wen-Ming Cao 5 , Yu-Xiong Feng 6
Affiliations
Abstract
Endoplasmic reticulum (ER) is the critical organelle that regulates essential cellular processes, including protein synthesis, folding, and post-translational modification, as well as lipid metabolism and calcium homeostasis. Disruption in ER homeostasis leads to a condition known as ER stress, characterized by the accumulation of misfolded or unfolded proteins. This triggers the unfolded protein response (UPR), an adaptive pathway mediated by three ER-resident sensors: inositol-requiring enzyme 1α (IRE1α), protein kinase R-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Increasing evidence highlights sustained UPR activation in malignant and immune cells within the tumor microenvironment (TME), which promotes tumor progression and metastasis while simultaneously impairing antitumor immunity. This review explores how UPR-driven intercellular signaling influences immunotherapy resistance, focusing on the alterations occurring in tumor cells as well as in the surrounding immune environment. By providing insights into these mechanisms, we aim to highlight the therapeutic potential of targeting the UPR pathways in modulating cancer immunity.
 
Murph said:
1. This one caught my eye because we seem to hear about extracellular matrix, actin and fibroactin so much these days; I'm always attracted to under-studied bits of the cell that people assume are just structural but could have functional properties that are overlooked.
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Me too. Long been interested in how the extra-cellular matrix is behaving mechanically in ME/CFS, including the so-called amorphous component. :geek:
 
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