MOTS-c peptide: mitochondrial research, evidence and UK status

Research-use notice: this article is for legitimate laboratory and educational research only. It does not provide guidance for human use, administration, dosing or treatment.

MOTS-c is a 16-amino-acid peptide encoded within the 12S rRNA gene of mitochondrial DNA, first described by Lee and colleagues in Cell Metabolism in 2015. Most of its research record is cell and mouse work on metabolism and exercise capacity, plus observational measurements in people. We have found no published efficacy trial of MOTS-c in humans, it is not a licensed medicine, and the World Anti-Doping Agency (WADA) names it on its 2026 Prohibited List.

What is MOTS-c?

MOTS-c stands for mitochondrial open reading frame of the 12S rRNA-c. Mitochondria, the structures that produce most of a cell’s energy, carry their own small genome. Lee and colleagues found a short open reading frame inside the mitochondrial gene for 12S ribosomal RNA (rRNA) that codes for a 16-amino-acid peptide, which a 2022 review gives as MRWQEMGYIFYPRKLR. The 2015 authors detected MOTS-c in mouse and rat tissues and in human and rodent plasma, and identified skeletal muscle as its apparent primary target organ.

MOTS-c belongs to a small group known as mitochondrial-derived peptides (MDPs), which also includes humanin. These are peptides coded by mitochondrial DNA that are studied as possible signalling molecules, rather than as parts of the energy-producing machinery itself.

How is MOTS-c thought to work?

In cultured cells, Lee and colleagues reported that MOTS-c inhibited part of folate metabolism. That led to a build-up of AICAR, an intermediate in purine synthesis, and to activation of AMP-activated protein kinase (AMPK), an enzyme that senses a cell’s energy status. A 2018 follow-up in the same journal by Kim and colleagues reported that, under metabolic stress, MOTS-c moved into the cell nucleus in an AMPK-dependent way, bound to chromatin and regulated nuclear gene expression. Both are cell-level mechanisms.

What does MOTS-c research show?

The table lists the main studies and the evidence level of each. The mechanistic work is in cells and mice; the human data are observational or concern a related molecule.

Cell and mouse studies

In the 2015 paper, mice fed a high-fat diet and older mice that were given MOTS-c showed higher insulin sensitivity than controls. A 2021 study in Nature Communications by Reynolds and colleagues reported higher scores on physical tests, including treadmill running, in mice given MOTS-c at 2, 12 and 22 months of age than in controls, and greater physical capacity in old mice when exposure began late in life.

Mouse studies use controlled genetics, diets and housing. They show how MOTS-c behaves as an experimental tool in that system, not what it would do in a person.

Human observational data

In the same 2021 study, 10 healthy young men who did not exercise regularly gave muscle and blood samples at rest and after a session of stationary cycling. MOTS-c levels rose 11.9-fold in skeletal muscle and 1.5–1.6-fold in plasma.

A 2019 cross-sectional study in Frontiers in Endocrinology measured serum MOTS-c and humanin in 225 adults in Qatar aged 30–75. MOTS-c was lower in people with type 2 diabetes than in controls and correlated negatively with glycated haemoglobin (HbA1c) and glucose, although in the multivariate analysis only humanin was independently associated with HbA1c.

Genetics adds another angle. A 2021 study in Aging by Zempo and colleagues examined m.1382A>C, an East Asian-specific mitochondrial DNA variant that changes lysine to glutamine at position 14 of MOTS-c (K14Q). In a meta-analysis of Japanese cohorts, the variant was associated with a higher prevalence of type 2 diabetes in men but not in women. In cells, the K14Q form showed reduced insulin-sensitising activity, and in male mice on a high-fat diet it did not show the glucose-tolerance changes reported for the usual form.

These are associations. They show that MOTS-c is measurable in people and varies with exercise, metabolic disease and genotype. They do not test what giving MOTS-c would do.

Early-phase clinical work

We have found no published human trial of MOTS-c itself. CB4211, described by its developer CohBar as an analogue of MOTS-c, was tested in a phase 1a/1b study registered as NCT03998514, which enrolled 88 participants, including adults with non-alcoholic fatty liver disease. Its primary outcomes were safety and tolerability at several dose levels. A 2021 sponsor press release reported no serious adverse events, but the registry shows no posted outcome data and we have not found a peer-reviewed report. An analogue is a different molecule, so its data do not transfer to MOTS-c.

When MOTS-c was nominated for use in US pharmacy compounding, the Food and Drug Administration (FDA) said it had not identified any human exposure data on drug products containing it. The nomination was later withdrawn.

MOTS-c vs SS-31 (elamipretide): what is the difference?

Both are called “mitochondrial peptides”, but they are different kinds of molecule with very different evidence bases.

Elamipretide, first studied as SS-31, is a mitochondria-targeted tetrapeptide that interacts with cardiolipin. A trial published in Genetics in Medicine in 2021 studied it in Barth syndrome, a rare genetic disorder of cardiolipin metabolism. In the randomised, double-blind, placebo-controlled crossover phase with 12 participants, neither primary endpoint was met. The open-label extension that followed reported changes in six-minute walk distance and on a symptom scale.

On 19 September 2025 the FDA granted accelerated approval to Forzinity (elamipretide) as the first treatment for Barth syndrome, in a defined patient group. The approval rests on knee-extensor muscle strength, an intermediate endpoint, and the FDA requires a randomised, double-blind, placebo-controlled confirmatory trial. In January 2026 the sponsor said it planned to start that trial in the first half of 2026. As of October 2026 we have found no other FDA approval for elamipretide and no UK marketing authorisation.

The two are not interchangeable. A US approval of elamipretide for one rare disease says nothing about MOTS-c, and research-grade SS-31 is not the approved medicine, which the FDA label describes as a hydrochloride salt. Salt form is worth checking on any batch report; see our guide to peptide counterions.

Thistle supplies MOTS-C — 10mg Research Peptide at £24.99 and SS-31 (Elamipretide) — 10mg Research Peptide at £26.99, each with a batch laboratory report.

How to check a MOTS-c or SS-31 batch

Both are short peptides, so the usual identity questions apply, plus one specific to each. When you read a batch laboratory report, check:

• Identity by mass spectrometry (MS), matching the expected mass of the full sequence. A high-performance liquid chromatography (HPLC) retention time alone does not establish identity.
• Sequence confirmation for MOTS-c. The natural K14Q variant swaps lysine for glutamine, and the two residues differ in mass by less than 0.04 Da. A low-resolution mass check cannot tell them apart; fragmentation (MS/MS) or high-resolution data can.
• Stereochemistry for SS-31. Its first residue is D-arginine. A mass spectrum cannot distinguish D and L forms, so confirming it needs a chiral method.
• Purity read correctly. An HPLC area percentage describes a separation. Closely related impurities, such as sequences missing one residue, can sit near the main peak.
• The batch number, method and date, matching the vial label.

For the general method, see HPLC vs mass spectrometry, peptide sequence impurities and How to read a peptide COA (certificate of analysis). Thistle publishes the laboratory report for the current batch on each product page, and you can look up any batch on our batch report lookup. Both are supplied as lyophilised (freeze-dried) powders; our peptide storage guide covers handling.

Is MOTS-c legal in the UK?

MOTS-c is not a licensed medicine in the UK, and we have found no UK marketing authorisation for it. The US Anti-Doping Agency (USADA) notes that it is not approved by the FDA for use in humans. It is supplied as a research material for laboratory use.

Presentation matters. Under the Human Medicines Regulations 2012, a product presented as treating or preventing disease in people, or used to restore, correct or modify physiological functions, is a medicinal product. The Medicines and Healthcare products Regulatory Agency (MHRA) judges presentation from all claims made for a product, including on websites and social media, and in April 2026 it said that if clinics make medicinal claims for peptide treatments, those products will be considered medicines. That is why this article describes research only. The US approval of elamipretide does not extend to the UK.

In sport, MOTS-c is named on WADA’s 2026 Prohibited List under S4.4 metabolic modulators, as an example of an activator of AMP-activated protein kinase (S4.4.1), and is prohibited at all times.

This section is general information, not legal advice.

MOTS-c FAQs

What does MOTS-c stand for?

Mitochondrial open reading frame of the 12S rRNA-c. The name describes where the peptide is encoded: a short reading frame inside the mitochondrial gene for 12S ribosomal RNA.

Is MOTS-c the same as SS-31?

No. MOTS-c is a natural 16-amino-acid peptide encoded in mitochondrial DNA. SS-31 (elamipretide) is a synthetic tetrapeptide that interacts with cardiolipin, and it has US accelerated approval for Barth syndrome.

Is MOTS-c banned in sport?

Yes. WADA’s 2026 Prohibited List names MOTS-c under S4.4 metabolic modulators as an AMPK activator, prohibited at all times.

Does MOTS-c have side effects?

There are no human safety data for MOTS-c research material, and the FDA has said it has not identified human exposure data for drug products containing it. The only early clinical safety work we found concerned an analogue, CB4211, with no peer-reviewed report. MOTS-c is not for human use, and we cannot advise on personal use.

How much does MOTS-c cost in the UK?

Prices vary by supplier. At the time of writing, Thistle sells MOTS-c 10mg at £24.99. Price says nothing about content or purity, so check the batch report.

Sources

• Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c in cells and mice (2015). Cell Metabolism. 2015;21(3):443–454. Cultured cells and mouse models.
• Kim KH, Son JM, Benayoun BA, Lee C. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell Metabolism. 2018;28(3):516–524.e7. Cultured cells.
• Reynolds JC, Lai RW, Woodhead JST, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications. 2021;12:470. Mouse models; small human exercise study.
• Ramanjaneya M, Bettahi I, Jerobin J, et al. Mitochondrial-Derived Peptides Are Down Regulated in Diabetes Subjects. Frontiers in Endocrinology. 2019;10:331. Human cross-sectional study.
• Zempo H, Kim SJ, Fuku N, et al. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging (Albany NY). 2021;13(2):1692–1717. Human cohorts, cells and mice.
• Mohtashami Z, Singh MK, Salimiaghdam N, Ozgul M, Kenney MC. MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases. International Journal of Molecular Sciences. 2022;23(19):11991. Review.
• ClinicalTrials.gov. NCT03998514: phase 1a/1b study of the safety, tolerability and pharmacokinetics of CB4211. Sponsor CohBar, Inc. Trial registration; no outcome data posted.
• CohBar, Inc. CB4211 phase 1a/1b topline announcement. 10 August 2021. Sponsor press release.
• Thompson WR, Hornby B, Manuel R, et al. A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism. Genetics in Medicine. 2021;23(3):471–478. Human trial.
• US Food and Drug Administration. FDA grants accelerated approval to first treatment for Barth syndrome. 19 September 2025. Press announcement.
• US Food and Drug Administration. Forzinity (elamipretide) prescribing information. Revised September 2025. Approved product label.
• Stealth BioTherapeutics. Stealth BioTherapeutics Provides Commercial and R&D Pipeline Update and Outlines 2026 Strategic Priorities. 6 January 2026. Sponsor press release.
• US Food and Drug Administration. Certain bulk drug substances for use in compounding that may present significant safety risks. Page updated April 2026.
• World Anti-Doping Agency. Prohibited List 2026. S4.4 metabolic modulators: activators of AMP-activated protein kinase.
• US Anti-Doping Agency. What is the MOTS-c peptide? Updated August 2026.
• legislation.gov.uk. The Human Medicines Regulations 2012, regulation 2: medicinal products.
• Medicines and Healthcare products Regulatory Agency. MHRA Guidance Note 8: A guide to what is a medicinal product. September 2025.
• Aesthetics Journal. MHRA investigates clinics following peptide claims. 15 April 2026.

Published by Thistle BioLabs, a UK supplier of research materials. This article summarises external research, not studies conducted by Thistle. Educational information only; no medical advice or recommendation for personal use.