Scientifically reviewed by Dr Stephan Hansberg
MOTS-c peptide: structure, research and legal status (2026)
MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA. Its identity data, discovery in 2015, what has been studied in cell, animal and human samples, the July 2026 FDA advisory review and its WADA status.
Key takeaways
- •MOTS-c is a 16-amino-acid peptide (MRWQEMGYIFYPRKLR) encoded by a short open reading frame inside the mitochondrial 12S rRNA gene.
- •It was first described in 2015 in Cell Metabolism, in cell and mouse studies of metabolic signalling.
- •Human data so far are mainly measurements of circulating or muscle MOTS-c, plus a completed Phase 1 trial of CB4211, an analogue developed from MOTS-c.
- •In July 2026 FDA staff proposed not adding MOTS-c to the 503A bulks list; the advisory committee voted 7-5 to recommend it, and rulemaking was still pending in October 2026.
- •WADA names MOTS-c under S4.4.1 (metabolic modulators), prohibited at all times. Celyfe does not sell MOTS-c.
What is MOTS-c?
MOTS-c is a 16-amino-acid peptide encoded not in the cell nucleus but in mitochondrial DNA, inside the gene for the 12S ribosomal RNA. Its name stands for mitochondrial open reading frame of the 12S rRNA-c. It belongs to a small group called mitochondrial-derived peptides and is studied as a signal between the mitochondria and the rest of the cell, particularly in metabolic research.
Almost all of the research so far is in cell cultures and mouse models, with some human observational data. MOTS-c is not an approved medicine, and its regulatory position moved in 2026 because of an FDA advisory committee review.
Identity at a glance
Identifiers checked against PubChem and the FDA's July 2026 briefing document.
| Property | MOTS-c |
|---|---|
| Aliases | Mitochondrial open reading frame of the 12S rRNA-c; MOTS-c (human) |
| Sequence (16 aa) | H-Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg-OH (MRWQEMGYIFYPRKLR) |
| Molecular formula | C101H152N28O22S2 |
| Molar mass | 2174.6 g/mol (free base) |
| CAS number | 1627580-64-6 |
| PubChem CID | 146675088 |
| FDA UNII | A5CV6JFB78 |
| Salt forms reviewed by FDA | MOTS-c (free base) and MOTS-c acetate |
Origin and discovery
MOTS-c was reported in 2015 by Lee and colleagues in Cell Metabolism. The group identified a short open reading frame within the mitochondrial 12S rRNA gene that encodes the 16-amino-acid peptide. In cell experiments it was linked to the AMPK pathway, and in mice it was studied in diet-induced obesity and insulin resistance models.
In 2018 Kim and colleagues reported that MOTS-c can move into the nucleus under metabolic stress and influence nuclear gene expression in cell models, which is why it is often described as a mitochondrial signal to the nucleus. A 2021 study by Reynolds and colleagues looked at MOTS-c in relation to exercise and age-related physical decline in mice, alongside measurements in human muscle and plasma samples.
What has been studied, by model
Representative published work is below. Model type is stated for every row; human rows are observational measurements, not treatment studies.
| Research area | Model | Example study (year, PMID) |
|---|---|---|
| Discovery, AMPK signalling, diet-induced obesity model | Cell and animal (mouse) | Lee et al., Cell Metab (2015), PMID 25738459 |
| Nuclear translocation under metabolic stress | Cell | Kim et al., Cell Metab (2018), PMID 29983246 |
| Circulating MOTS-c and insulin sensitivity | Human (observational) | Cataldo et al., J Investig Med (2018), PMID 29593067 |
| Exercise and age-dependent physical decline | Animal (mouse) plus human samples | Reynolds et al., Nat Commun (2021), PMID 33473109 |
| Aged placenta-derived mesenchymal stem cells | Human cells in vitro | Yu et al., Mitochondrion (2021), PMID 33639272 |
| Overview of mitochondrial-derived peptides | Review | Merry et al., Am J Physiol Endocrinol Metab (2020), PMID 32776825 |
Human trial status
We could not identify a completed, peer-reviewed treatment trial of native MOTS-c. The closest registered programme is CB4211, a peptide CohBar described as developed from MOTS-c, which completed a Phase 1a/1b study in healthy volunteers and people with non-alcoholic fatty liver disease (NCT03998514). An analogue is a different molecule, so results for CB4211 cannot be read across to MOTS-c itself.
The FDA's July 2026 briefing document stated that there were no clinical studies to assess the safety and effectiveness of MOTS-c-related substances in humans, and no available nonclinical data to inform safety for the proposed uses.
Regulatory status in 2026
MOTS-c was one of seven peptides reviewed by the FDA's Pharmacy Compounding Advisory Committee on 23 and 24 July 2026. The nominations had been withdrawn, but the FDA chose to present them anyway, and FDA staff proposed that neither MOTS-c free base nor MOTS-c acetate be added to the 503A bulks list. The committee voted 7-5 with two abstentions to recommend it. The vote is advisory; as of October 2026 the FDA had not completed rulemaking.
| Authority | Status (checked October 2026) |
|---|---|
| US FDA | Not an approved drug. PCAC recommended adding MOTS-c to the 503A bulks list (7-5, 2 abstentions) against the FDA staff proposal; rulemaking pending. |
| UK MHRA | No UK marketing authorisation. Medicines law applies if it is supplied for human use. |
| AU TGA | Not named in the Poisons Standard (October 2026 instrument). General rules for unapproved therapeutic goods still apply. |
| WADA 2026 | Named under S4.4.1 (metabolic modulators, AMPK activators), prohibited at all times. |
Stability and handling notes
MOTS-c carries two methionines (positions 1 and 6) and a tryptophan (position 3), all residues that are prone to oxidation, so oxidised variants are a realistic impurity class. It is also strongly basic, with three arginines and a lysine, which affects how it behaves in chromatography and which counter-ion it is supplied as.
The FDA's briefing noted that suppliers sell both a free base and an acetate salt and that the nomination package was inconsistent about which form was meant. For any MOTS-c material, the certificate should state the form, the identity method and the purity method.
Open questions
How a peptide encoded in mitochondrial DNA is translated and exported, what its receptor or binding partners are, and whether the associations seen in human observational data are causal are all unresolved. The FDA's review also highlighted the absence of nonclinical safety data for the uses proposed for compounding.
Where Celyfe fits
Celyfe does not sell MOTS-c. The closest compound in the range, by research context, is NAD+, the central redox coenzyme of mitochondrial metabolism: it cycles between NAD+ and NADH in the citric acid cycle and oxidative phosphorylation, and is the substrate for sirtuins and PARPs.
The NAD+ Precision Pen (/products/nad-precision-pen) holds NAD+ 500mg in a pre-filled 3ml cartridge. Its batch certificate (batch A26085, Analiza Bialek, HPLC, 99% purity, dated 2 October 2026) is in the COA library at /coa. Our guide what is NAD+ covers the molecule itself.
Sources
Primary and official sources checked October 2026:
- PubChem: MOTS-c, CID 146675088 (pubchem.ncbi.nlm.nih.gov)
- Lee C et al. The mitochondrial-derived peptide MOTS-c and metabolic homeostasis (cell and mouse study). Cell Metab, 2015. PMID 25738459
- Kim KH et al. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab, 2018. PMID 29983246
- Cataldo LR et al. Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. J Investig Med, 2018. PMID 29593067
- Reynolds JC et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun, 2021. PMID 33473109
- Yu WD et al. MOTS-c in aged human placenta-derived mesenchymal stem cells in vitro. Mitochondrion, 2021. PMID 33639272
- Merry TL et al. Mitochondrial-derived peptides in energy metabolism. Am J Physiol Endocrinol Metab, 2020. PMID 32776825
- ClinicalTrials.gov: NCT03998514, Phase 1a/1b study of CB4211 (CohBar, Inc.)
- FDA: Briefing document for MOTS-c-related bulk drug substances, Pharmacy Compounding Advisory Committee, 23-24 July 2026 (fda.gov)
- AJMC: FDA panel backs 6 peptides for compounding, 31 July 2026
- Therapeutic Goods (Poisons Standard, October 2026) Instrument 2026, F2026L01327 (legislation.gov.au)
- WADA: Prohibited List 2026, in force 1 January 2026 (wada-ama.org)
Research use only
Celyfe supplies research peptides for laboratory and research use only. Nothing on this page is guidance on use in humans or animals.
Research updates
Peptide research and testing, in your inbox
New batch certificates, regulation changes and a monthly digest of new published research on the compounds we cover. No spam, unsubscribe at any time.