In my previous post, we looked at how the new WASF3 brain study creates a fascinating bridge to historical ME/CFS transcriptomic data, showing a cellular energy crisis driven by the IER3 (IEX-1) mitochondrial brake. To understand why this communication line fails, we have to look closer at the physical structures where this breakdown occurs.
This brings me back to a blog post I wrote all the way back in October, 2018 ("PACS2 and ME"). Back then, we explored how the endoplasmic reticulum (ER) and mitochondria are tubular organelles with a characteristic “network structure” that facilitates the formation of inter-organellar connections. We discussed how mitochondria-associated ER membranes (MAMs), a subdomain of the ER that is tightly linked to and communicates with mitochondria, serve multiple physiological functions including lipid synthesis and exchange, calcium signaling, bioenergetics, and apoptosis.
In that 2018 post, I noted that abnormalities and dysfunction of MAMs are involved in various neurodegenerative disorders including Alzheimer’s, ALS, and Parkinson’s disease [1]. With the publication of the new WASF3 data, it is highly compelling to hypothesize that ME/CFS belongs on this exact same list of structural MAM pathologies.
The Dynamic Switch in the Middle of the Bridge
As we reviewed via Figure 1 from Liu and Zhu (2017) in that post, several protein complexes physically tether these organelles together [1]. One of the key players highlighted was phosphorin acidic cluster sorting protein 2 (PACS2), which modulates the crucial Fis1-Bap31 tether [1].
As a multifunctional protein, PACS2 is involved in membrane trafficking, MAM-localized Ca²⁺ signaling, apoptosis, lipid metabolism, and regulating the p53-p21-dependent cell cycle arrest [2]. Essentially, PACS2 functions as a metabolic switch that integrates traffic and interorganellar communication with nuclear gene expression in response to anabolic or catabolic cues [2].
When we connect my 2018 post with the new WASF3 brain study, the pieces of the puzzle begin to interlock beautifully:
- The WASF3 Connection: The new study reveals that WASF3 localizes precisely at these MAM interfaces. When cell stress causes an accumulation of WASF3, it throws a wrench into the delicate signaling across the bridge, triggering a p53-mediated stress cascade.
- The PACS2 Control Gate: Because PACS2 directly governs the p53-p21 stress response, lipid metabolism, and calcium flux at the MAM interface [2], any disruption to PACS2 will destabilize the entire bridge. This leaves the mitochondria completely exposed to downstream suppression, such as the IER3 energy brake running in high gear.
Epigenetic Scars and Viral Hijacking
Back in 2018, I highlighted a profound clue from de Vega et al. (2018): the gene PACS2 (TSS1500) is differentially methylated in immune cells from ME/CFS patient subtypes [3]. Because methylation acts as the cell’s internal volume control, an altered methylation profile means the cell cannot properly regulate this master metabolic switch at the MAM bridge.
What initially caused the dysregulation of the PACS2 signaling pathway? As previously noted, viruses can hijack this pathway, targeting the ER-mitochondria interface to manipulate cellular bioenergetics and evade immune responses. These findings support a compelling hypothesis: an acute viral infection—the classic trigger for ME/CFS—may permanently impair the PACS2 pathway by leaving a lasting epigenetic mark on the MAM interface.
References (from the original 2018 post):
- Liu and Zhu (2017). Endoplasmic reticulum-mitochondria tethering in neurodegenerative diseases. Transl Neurodegener. 6: 21. [PMC5567882].
- Thomas et al. (2017). Caught in the act - protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease. J Cell Sci. 130(11):1865-1876. [PMC5482974].
- de Vega et al. (2018). Integration of DNA methylation & health scores identifies subtypes in ME/CFS. Epigenomics, 10(5).
