MOTS-c: clinical evidence record
Also known as: Mitochondrial Open Reading Frame of the 12S rRNA-c, MOTSc
Oliver Mackman · Editorial director · Best Business Loans Ltd (16833937)
Last updated 2026-05-22
Independent, and paid nothing. We take no commission, no referral fee and no payment from any retailer, clinic or pharmacy on this site. Outbound links are ordinary untracked links. How we are funded.
AI-friendly summary · MOTS-c
Discovered by the Cohen lab at USC in 2015. Preclinical mouse evidence for AMPK activation, insulin sensitisation, and exercise capacity. Early-phase human pharmacokinetic and pilot-study work has begun. No phase III human RCTs published.
Mechanism of action
How MOTS-c works
16-amino-acid mitochondrial-derived peptide encoded within the 12S rRNA region of mitochondrial DNA. Proposed to activate AMP-activated protein kinase (AMPK), regulate metabolic homeostasis, and influence glucose uptake and insulin sensitivity in preclinical models.
Top peer-reviewed citations
Selection of the most-cited peer-reviewed literature on MOTS-c. Where a verified PMID or DOI is shown, the citation links to the original record. Other citations list the title, authors, journal and year so the reader can locate the paper through the journal index or the PubMed search linked below. PeptideClear publishes editorial commentary, not clinical guidance.
-
The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance
Lee C, Zeng J, Drew BG, et al.. Cell metabolism, 2015.
-
MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
Reynolds JC, Lai RW, Woodhead JST, et al.. Nature communications, 2021.
-
Mitochondrial-Derived Peptides Are Down Regulated in Diabetes Subjects
Ramanjaneya M, Bettahi I, Jerobin J, et al.. Frontiers in endocrinology, 2019.
-
The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan
Yen K, Mehta HH, Kim SJ, et al.. Aging, 2020.
-
MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
Reynolds JC, Lai RW, Woodhead JST, et al.. Nature communications, 2021.
-
Mitochondrial-derived peptides in energy metabolism
Merry TL, Chan A, Woodhead JST, et al.. American journal of physiology. Endocrinology and metabolism, 2020.
-
The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity
Cataldo LR, Fernandez-Verdejo R, Santos JL, Galgani JE. Physiological reports, 2019.
-
Mitochondrially derived peptides as novel regulators of metabolism
Kim SJ, Xiao J, Wan J, Cohen P, Yen K. The Journal of physiology, 2017.
-
The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress
Kim KH, Son JM, Benayoun BA, Lee C. Cell metabolism, 2018.
-
MOTS-c: How a secreted mitochondrial microprotein may become a potential treatment for inflammatory lung diseases
Amado CA, Agüero J, García-Unzueta M, et al.. Journal of translational medicine, 2026.
-
MOTS-c preserves mitochondrial subpopulation bioenergetics and genome integrity to attenuate cardiac ischemia reperfusion injury
Santhanam SS, Jayaraman S, Rajesh SS, et al.. Molecular biology reports, 2026.
-
Humanin and MOTS-c Attenuate Atrial Fibrillation by Suppressing Fibrosis and Mitochondrial Dysfunction
Liao Y, Xu J, Jiao Y, et al.. Biomedicines, 2026.
-
Reduced Circulating MOTS-c Levels in Hashimoto's Thyroiditis Reflect Integrated Autoimmune and Metabolic Dysregulation: A Cross-Sectional Study
Sonay HO, Duran EN, Algemi M, et al.. Journal of clinical medicine, 2026.
-
MOTS-c partially protects against skeletal muscle deterioration in C26 cachexia
Jamnick NA, Livingston PD, Gammon CJ, et al.. Frontiers in medicine, 2026.
Full PubMed search: https://pubmed.ncbi.nlm.nih.gov/?term=MOTS-c+mitochondrial+peptide.
Registered clinical trials
As of 2026-07-13, MOTS-c has 7 interventional trials listed on ClinicalTrials.gov and the ISRCTN registry. Registration means a study is planned, running or completed. It is not evidence of efficacy, and a listing is not an endorsement.
Source: ClinicalTrials.gov and the ISRCTN registry, refreshed 2026-07-13. See the peptide clinical-trials tracker for the full picture across compounds.
UK regulatory status
Plain-English summary of where MOTS-c sits under the four UK and international frameworks that govern peptide supply. Editorial commentary, not legal advice.
- Misuse of Drugs Act 1971: Not controlled under the Misuse of Drugs Act 1971.
- Psychoactive Substances Act 2016: Not scheduled under the Psychoactive Substances Act 2016.
- MHRA medicines classification: No UK marketing authorisation as a medicine.
- WADA Prohibited List: WADA Prohibited List S4 (hormone and metabolic modulators), prohibited at all times.
Full regulatory record: MOTS-c UK regulatory status.
Risks and unknowns
What the literature does not yet show about MOTS-c
Known concerns
- The evidence for MOTS-c is mixed: some human data exists alongside a larger preclinical literature. Mixed evidence is easy to quote selectively, so check whether a claim you have read rests on the human work or the animal work.
- 7 registered interventional trials exist for MOTS-c and 6 are recruiting, so the evidence base is actively moving. A registration is not a result, and a recruiting trial has by definition not reported.
- MOTS-c holds no UK marketing authorisation, so nothing you can buy has been assessed by a regulator, released by batch, or dispensed by an accountable pharmacy. Purity, dose accuracy and sterility rest entirely on the seller's own documentation.
Open questions in the literature
- Long-term outcomes beyond the duration of the published trials are unknown, and the published trials are considerably shorter than the periods over which people actually use these compounds.
- Interactions between MOTS-c and prescribed medicines are not systematically studied, which matters most for anyone already on treatment for a long-term condition.
- Effects on body composition, and whether any change is maintained after stopping, are among the least well characterised parts of the metabolic literature.
Regulatory note
No UK marketing authorisation as a medicine. Prohibited at all times under WADA S4 (hormone and metabolic modulators). The moment a UK seller or commentator makes a therapeutic claim, MHRA can treat the product as an unlicensed medicinal product.
Important: PeptideClear publishes encyclopedia commentary only and does not recommend human use. Speak to a UK-registered prescriber before any medical decision.
Related reading on PeptideClear
Frequently asked questions
What is the evidence level for MOTS-c?
What is the UK regulatory status of MOTS-c?
Has MOTS-c been tested in human clinical trials?
Where can I read the source literature for MOTS-c?
Last verified 2026-05-22. Editorial commentary, not legal or clinical advice. Citations without a linked identifier can be located through the PubMed search and the journal index.