Systematic Examination of Gene Expression and Proteomic Evidence Across Tissues Supports the Role of Mitochondrial Dysregulation in ME/CFS, 2026

[TiredMathematician]

Systematic Examination of Gene Expression and Proteomic Evidence Across Tissues Supports the Role of Mitochondrial Dysregulation in ME/CFS

Spoiler: Authors

Keele, Gregory R.; Enger, Mike; Barnette, Quinn; Ruiz-Esparza, Roman; Alvarado, Manuel; Mathur, Ravi; Stratford, Jeran K.; Giamberardino, Stephanie N.; Brown, Linda Morris; Webb, Bradley T.; Carnes, Megan Ulmer

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, multisystem disease characterized by post-exertional malaise and persistent fatigue. The cause of ME/CFS is not well understood, and there are no established biomarkers or FDA-approved pharmacotherapies. The clinical heterogeneity of ME/CFS presents challenges to diagnosis and treatment and necessitates collaborative efforts to generate robust findings. This study leveraged gene and protein expression data from the mapMECFS data repository and the DecodeME Genome-Wide Association Study (GWAS) to assess consistent gene signatures across studies. The mitochondrial genes MT-RNR1 and MT-RNR2 exhibited lower expression in ME/CFS cases in two studies. Combining this with increased expression of mitochondrial genes in platelets from another study, this supports mitochondrial dysregulation as having a role in ME/CFS. Furthermore, ME/CFS-associated genes were mapped to compounds in drug databases as possible treatments for further investigation. In muscle gene expression data, 107 approved compounds target 26 genes with functions relevant to mitochondrial support and immunomodulators. From the DecodeME GWAS, 83 approved compounds target 24 genes with functions related to energy metabolism and mitochondrial function. Though little consistency in specific genes was observed across studies, which highlights the need for larger studies, mitochondrial dysfunction in ME/CFS cases was evident across studies.

Web | DOI | International Journal of Molecular Sciences

 

[Jonathan Edwards]

I am not familiar with these authors. They mention DecodeME but the claim seems to be based on gene expression rather than genetics. It seems a bit of a stretch to write a opinion paper based on some findings like this.

 

[Jaybee00]

Opipramol comes up again. Hmmmm.

 

[DMissa]

“MT-RNR1 and MT-RNR2 encode for the 12S and 16S rRNA in the mitochondrial genome and showed lower expression in ME/CFS cases compared to controls across two studies, notably in PBMC [18] and monocytes derived from PBMC [19] (Figure 2).”

We have discussed to death that mitochondrial measurements from mixed PBMC are uninterpretable because different immune cell subsets carry and use more or less mitochondria.

More to the point, mixed PBMC to monocytes can’t easily be compared directly and then interpreted as having the same things happening in terms of a disease process based on gene expression.

This isn’t really biologically coherent.

I have scanned the rest of the results and found that it is painted in similarly broad strokes of “mitochondrially encoded genes keep popping up”. I don’t know what it means.

 

[Jonathan Edwards]

And lower expression might indicate a normal response to something else rather than 'dysregulation' I suspect.

 

[ME/CFS Science Blog]

Think the main conclusion was (or should be) that there's a lack of overlap between what these studies found. Even with a lenient false discovery rate (FDR) of 10%, there were only 2 study that pointed to similar genes.

In this case it was MT-RNR1 and MT-RNR2 which came up in the Raijmakers (N= 10) and Gamer studies (N = 33). These genes were lower in ME/CFS patients but the samples sizes of these studies are probably too low to take this very seriously.



The rest is mainly just speculation by setting the FDR even lower to 30%, and selecting about repurposed drugs that might impact one of the hundreds of genes that might be implicated in DecodeME or the Walitt et al. NIH study but about which we are highly uncertain. The Walitt et al. study had 13 patients for the muscle analysis but this study extracted 246 potentially implicated genes from this.

 

[forestglip]

This study is helpful because they compiled transcriptomics and proteomics results from several studies into one file, Supplementary File S2. It makes it easier to cross-check expression findings in older studies in the future.

For example, here are the differentially expressed proteins for Germain 2021:

The seven studies they've reanalyzed to create the dataset are in Table 1:

• Vu et al. 2024
• Van Booven et al. 2023/Gamer et al. 2023
• Walitt et al. 2024 (Transcriptomics)
• Walitt et al. 2024 (Proteomics)
• Raijmakers et al. 2019
• Germain et al. 2021
• Giloteaux et al. 2023

 

[Sean]

And lower expression might indicate a normal response to something else rather than 'dysregulation' I suspect.

It remains my view that the vast majority, perhaps even all, of everything we currently 'know' about ME/CFS is just the downstream secondary and typically contingent consequences of the as yet unidentified primary underlying pathology.

All of what we are seeing so far is just the normal physiology attempting to cope with and adapt to pathological demands on it that are outside its sustainable normal operating parameters.

What is imposing those demands is the unknown.