Review Redefining Mitochondrial Therapy for ME/CFS: The Case for MOTS-c, 2025, Klimas et al

[John Mac]

https://www.preprints.org/manuscript/202507.0058/v1

Abstract​

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating, multi-system disease characterized by profound fatigue, post-exertional malaise (PEM), and a constellation of immune, neurological, and autonomic symptoms.
Despite its global prevalence, the pathophysiology of ME/CFS remains elusive, and there are no FDA-approved treatments targeting the underlying mechanisms.
Symptom-based pharmacologic management is often complicated by hypersensitivity reactions and mitochondrial toxicity.
Non-pharmacologic interventions, such as energy conservation, autonomic regulation, and nutritional strategies, are frequently employed to mitigate symptom burden.
Emerging research points to mitochondrial dysfunction as a core contributor to ME/CFS pathology, marked by impaired ATP production, oxidative stress, and bioenergetic failure.
Mitochondrial-derived peptides (MDPs), particularly MOTS-c, offer a novel therapeutic avenue by enhancing mitochondrial biogenesis, reducing oxidative damage, and modulating inflammatory responses through AMPK and NRF2 activation.
Preclinical evidence suggests that MOTS-c improves glucose metabolism, increases mitochondrial density, and enhances fatigue resistance.
However, safety and efficacy data in humans are lacking.
Future investigations are needed to evaluate MOTS-c's potential as a disease-modifying therapy in ME/CFS.

 

[Jonathan Edwards]

Emerging research points to mitochondrial dysfunction as a core contributor to ME/CFS pathology, marked by impaired ATP production, oxidative stress, and bioenergetic failure.

I am not sure what the basis of any of that is?

 

[V.R.T.]

I have just googled this peptide and seen it is considered an exercise mimetic. Isn't there a possibility it could mimic the biological processes of exercise that trigger PEM, since we don't know what they are yet?

 

[Jonathan Edwards]

I have just googled this peptide and seen it is considered an exercise mimetic. Isn't there a possibility it could mimic the biological processes of exercise that trigger PEM, since we don't know what they are yet?

From what they say it seems likely to do the opposite of generating PEM.
But a malfunction of its signalling might be relevant I guess.
I think hypotheses around such things bneed to be much clearer about what it is they are supposed to explain and where. PEM is not a reduction in ATP in muscle, for instance.

 

[V.R.T.]

From what they say it seems likely to do the opposite of generating PEM.
But a malfunction of its signalling might be relevant I guess.
I think hypotheses around such things bneed to be much clearer about what it is they are supposed to explain and where. PEM is not a reduction in ATP in muscle, for instance.

So do you think there's a chance it could work then? Setting aside the unclear hypothesis/reasoning?

 

[forestglip]

I am not sure what the basis of any of that is?

Here is their reasoning, but probably look at my next post first.

2.2. Mitochondrial Dysfunction in ME/CFS
Although research on glycolytic flux and respiratory chain function in ME/CFS remains inconsistent, there is a growing consensus that mitochondrial dysfunction lies at the heart of the disease's pathophysiology. This dysfunction manifests as impaired ATP production, chronic oxidative stress, neuroinflammation, and broader metabolic imbalance [8,37]. Patients with ME/CFS frequently exhibit clinical features consistent with mitochondrial bioenergetic failure—such as profound fatigue, post-exertional malaise (PEM), and orthostatic intolerance—which are suggestive of poor energy recovery and cellular stress under low-grade exertion. Mitochondrial ultrastructural abnormalities have been reported in ME/CFS patients, including cristae branching, mitochondrial swelling, vacuolation, and the appearance of myelin figures, all of which indicate degenerative changes. However, these findings remain inconsistent and have not been uniformly verified across studies [38,39]. Despite this, functional studies—many of which assess metabolic responses to stressors or post-exertion—reveal patterns of impaired oxidative phosphorylation, altered redox status, and diminished energy generation [12,41].

A systematic review by Holden et al. examined studies comparing mitochondrial profiles of ME/CFS patients to healthy controls, using various case definitions (Fukuda, Canadian Consensus, International Consensus, and IOM). The review highlighted consistent findings of reduced mitochondrial enzyme activity, impaired ETC performance, diminished ATP synthesis, and altered mitochondrial density and morphology. Genetic contributions to these dysfunctions were also proposed, suggesting a possible heritable mitochondrial vulnerability in some patients [37]. Moreover, mitochondrial dysfunction is likely interlinked with neuroinflammation, which has been visualized via PET imaging in patients with ME/CFS and is believed to contribute to the fatigue, cognitive dysfunction, and sensory hypersensitivity reported in both ME/CFS and Long COVID [42,43].

References

8. Naviaux RK, Naviaux JC, Li K, et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci USA. 2016;113(37):E5472-E5480. [S4ME]

12. Bateman L, Bested A, Bonilla HF, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer. Front Pediatr. 2021;9:709276. [S4ME]

37. Osellame L, Blacker TS, Duchen MR. Cellular and molecular mechanisms of mitochondrial function. Biochim Biophys Acta. 2012;1820(5):787-802. [Article]

38. Nolfi Donegan D, Braganza A, Shiva S. Mitochondrial electron transport: Oxidative phosphorylation, mitochondrial oxidant production, and methods of measurement. Redox Biol. 2020;37:101674. [Article]

39. Carafoli E. Calcium transport and the mitochondria. Biochim Biophys Acta. 1979;516(1):1-6.

41. Papadopoulos V, Miller WL. Role of mitochondria in steroidogenesis. Endocr Rev. 2012;33(4):647-684. [Article]

42. Holden S. Mitochondrial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A systematic review and quality assessment of the evidence. J Transl Med. 2020;18:290. [S4ME]

43. Behan WM, More IA, Behan PO. Mitochondrial abnormalities in the postviral fatigue syndrome. Acta Neuropathol. 1991;83(1):61-65. [S4ME]

 

[forestglip]

There appear to be a lot of issues with the references. As in many don't seem to exist. I looked at the first 10, and couldn't find the following papers. I emailed Stephanie L. Grach, who has authored ME/CFS-related papers, about ref. 4, and she said she was not involved in that paper.

3. Richman S, Shekleton J. Pharmacologic treatment of ME/CFS-related cardiovascular dysfunction. J Clin Med. 2019;8(11):1802

4. Grach SL. Advances in cardiovascular pharmacology for postural orthostatic tachycardia syndrome (POTS). Auton Neurosci. 2023;245:103068.

5. Stoker ML, Reijne AC, Hellebrekers DM, et al. Impact of pharmaceuticals on mitochondrial function and implications for ME/CFS. Mitochondrion. 2019;46:220-228.

More minor issues

6. Janhsen K, Roser P, Hoff P. The problems of long-term treatment with benzodiazepines. Dtsch Arztebl Int. 2015;112(1-2):1-7.
- [This one just cuts off the end of the title from this paper.]

7. Bateman L, Bested A, Bonilla HF, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Diagnosis and Management in Young People: A Primer. Front Pediatr. 2021;9:709276.
- [Authors and year don't match paper. Same reference as number 12.]

10. Jason LA, Evans M, Brown M, Porter N, Brown A, Hunnell J. Fatigue Scales and Chronic Fatigue Syndrome: Issues of Sensitivity and Specificity. Disabil Stud Q. 2009;29(1)
- [Year doesn't match paper.]

Edit: Also, can't find this one from the post above:

39. Carafoli E. Calcium transport and the mitochondria. Biochim Biophys Acta. 1979;516(1):1-6.

 

[Jonathan Edwards]

So do you think there's a chance it could work then? Setting aside the unclear hypothesis/reasoning?

No idea, but I am not holding my breath.

 

[Jonathan Edwards]

Here is their reasoning, but probably look at my next post first.


References

OK. I think there is a failure to mention an awful lot of negative findings and a disconnect between physiology and symptoms.

 

[Jaybee00]

From google search:

AI-generated papers often face challenges with references due to the potential for generating fake or inaccurate citations, difficulty handling author name and DOI/URL formatting inconsistencies, and the risk of plagiarism when AI output is presented as original work.

Also

Fabrication and errors in the bibliographic citations generated by ChatGPT​

Fabrication and errors in the bibliographic citations generated by ChatGPT - Scientific Reports

Although chatbots such as ChatGPT can facilitate cost-effective text generation and editing, factually incorrect responses (hallucinations) limit their utility. This study evaluates one particular type of hallucination: fabricated bibliographic citations that do not represent actual scholarly...

www.nature.com

​

 

[forestglip]

From google search:

AI-generated papers often face challenges with references due to the potential for generating fake or inaccurate citations, difficulty handling author name and DOI/URL formatting inconsistencies, and the risk of plagiarism when AI output is presented as original work.

Yeah, looks like to me like AI was used for this paper. Similar to the recent US public health review:

- https://www.politifact.com/article/2025/may/30/MAHA-report-AI-fake-citations/

Multiple citations in the "Make America Healthy Again" report contained titles of nonexistent papers, or mischaracterized real ones. Experts say those are hallmarks of artificial intelligence generation.

 

[Nightsong]

In addition a number of references are also duplicated - e.g. 8, 9, 10 are duplicated as 13, 14, 15.

 

[Creekside]

Emerging research points to mitochondrial dysfunction as a core contributor to ME/CFS pathology, marked by impaired ATP production, oxidative stress, and bioenergetic failure.

When I read that, I just took it as someone choosing a hypothesis, for whatever reason, and then searching for any evidence that looked supportive. It's no better than astrology, cherrypicking some data to support "finding" patterns in random noise.

 

[Jonathan Edwards]

One of the things I have been finding with the simpleGoogle AI summary is that it is always positive about finding a result even if when you read through it is referring to data that are not that result. It seems a nice example of the 'artificial stupidity' that is an accurate replication of human muddle headed and biased thinking.

 

[forestglip]

Oh, the paper says:

Acknowledgments: During the preparation of this manuscript/study, the author(s) used [OpenAI] to assist in compiling relevant literature during the early stages of manuscript development; all sources were subsequently cross-checked through manual review and citation validation to ensure accuracy and scholarly rigor. The authors have reviewed and edited the output and take full responsibility for the content of this publication.

 

[Utsikt]

When I read that, I just took it as someone choosing a hypothesis, for whatever reason, and then searching for any evidence that looked supportive. It's no better than astrology, cherrypicking some data to support "finding" patterns in random noise.

It reminds me of most of the things we had to write for my economics degree. Just use google scholar to look for supporting citations, instead of trying to figure out what’s an accurate representation of the current knowledge. Relativism at its finest.

 

[Jaybee00]

Oh, the paper says:

 

[Jaybee00]

Lily T*hrani probably too busy working on her IG account to check the references.

 

[DMissa]

I was going to comment that the literature summary is factually incorrect in several areas… but then I saw “AI” was used… :/