MOTS-c is a 16-amino-acid peptide that is encoded not in the DNA of the cell nucleus but in the mitochondria’s own DNA, within the gene for 12S ribosomal RNA. Researchers at the University of Southern California first described it in 2015 [1]. Research on MOTS-c is still largely preclinical, meaning that it has mostly been carried out in cells and laboratory animals. MOTS-c is not a medicine and is on the World Anti-Doping Agency (WADA) Prohibited List [4].
A peptide from mitochondrial DNA
Mitochondria are the powerhouses of the cell and have their own small genome. For a long time, mitochondrial DNA was thought to code only for a handful of proteins and for the RNA molecules that the mitochondrion itself needs. After the discovery of humanin, a peptide encoded in a short open reading frame of mitochondrial DNA, researchers began looking for more peptides of this kind [1].
In this way, Lee and colleagues found a short open reading frame within the 12S rRNA gene in 2015. It encodes a 16-amino-acid peptide, which they named MOTS-c: mitochondrial open reading frame of the 12S rRNA-c [1]. MOTS-c therefore belongs to the group of mitochondrial-derived peptides (MDPs).
| Feature | MOTS-c |
|---|---|
| Length | 16 amino acids |
| Amino acid sequence | MRWQEMGYIFYPRKLR |
| Encoded in | mitochondrial gene MT-RNR1 (12S rRNA) |
| Molecular formula | C101H152N28O22S2 (PubChem CID 146675088) |
| First described | Lee et al., Cell Metabolism, 2015 |
| Form as research material | lyophilised (freeze-dried) powder |
The sequence and formula are taken from UniProt and PubChem [5]. The two sulphur atoms in the formula come from the two methionines (M) in the sequence.
What researchers investigate in MOTS-c
In the original publication, the researchers describe how, in cells, MOTS-c interferes with folate metabolism and the associated purine synthesis. This activates AMPK, an enzyme that monitors the cell’s energy status. In mice, skeletal muscle appeared to be the main target tissue [1].
A follow-up study from the same research group showed that in cell models under metabolic stress, such as glucose deprivation, MOTS-c moves from the cytoplasm into the cell nucleus. There, it influences the expression of nuclear genes, including genes containing an antioxidant response element, and interacts with the transcription factor NRF2 [2]. This was notable, as it was one of the first indications that a factor encoded in mitochondrial DNA actively regulates genes in the nucleus.
These mechanisms have been described in the literature, mainly in cell cultures and mice. Their relevance to humans has not been established.
Research status and open questions
Most research on MOTS-c is preclinical, consisting of cell and animal studies. In humans, it mainly consists of observational studies that measure the body’s own MOTS-c levels in the blood. Such measurements are harder than they look: a doping control laboratory in Cologne developed an LC-MS method (liquid chromatography with mass spectrometry) and was unable to confirm the values reported with a commercial ELISA test [3]. Reported blood levels therefore depend heavily on the measurement method.
Interventional clinical research is scarce. A derivative, CB4211, was studied by the company CohBar in a phase 1a/1b study (NCT03998514, completed). ClinicalTrials.gov also lists a phase 2 study of MOTS-c itself (NCT07505745), which is still recruiting participants. We do not discuss the outcomes of these studies here.
Open questions include how MOTS-c behaves in humans over the long term, how stable it is in the body and what safety data larger studies will yield.
Regulation and WADA status
No medicine containing MOTS-c has been authorised by the European Medicines Agency (EMA) or the US FDA. Clean Peptides therefore sells MOTS-c exclusively as research material (research use only).
On WADA’s 2026 Prohibited List, in force since 1 January 2026, MOTS-c is explicitly named in class S4 (hormone and metabolic modulators), under metabolic modulators [4]. Substances in class S4 are prohibited for athletes at all times, both in and out of competition. Doping control laboratories can detect MOTS-c and several of its breakdown products by mass spectrometry [3].
Quality and analysis of MOTS-c
- Identity. Mass spectrometry (MS) checks whether the measured mass matches the mass calculated from the 16-amino-acid sequence.
- Oxidation. MOTS-c contains two methionines and one tryptophan, which are sensitive to oxidation. An oxidised variant has a mass 16 daltons higher for each oxygen atom added and appears as a separate peak. The Cologne laboratory therefore included two oxidation products in its method [3].
- Purity. HPLC shows the proportion accounted for by the main peak. How to read this on a certificate of analysis is explained in How to read a certificate of analysis (COA).
- Storage. Dry, cool and dark, to limit oxidation and moisture uptake; see How to store peptides.
Every vial has a batch number on its label. Record it with every experiment, so that your results can always be traced back to a specific batch.
Products and further reading
Products
MOTS-c 10 mg is supplied as lyophilised powder in a vial. For reconstitution in the lab, bacteriostatic water 3 ml or 10 ml is sold separately.
Further reading
- What are peptides? Explanation and key terms
- What is NAD+? A coenzyme in research
- What is tesamorelin? The GHRH analogue explained
- Purity, endotoxins and heavy metals in peptides
Sources
- Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism 2015;21(3):443–454. doi:10.1016/j.cmet.2015.02.009
- 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. doi:10.1016/j.cmet.2018.06.008
- Knoop A, Thomas A, Thevis M. Development of a mass spectrometry based detection method for the mitochondrion-derived peptide MOTS-c in plasma samples for doping control purposes. Rapid Communications in Mass Spectrometry 2019;33(4):371–380. doi:10.1002/rcm.8337
- World Anti-Doping Agency. Prohibited List 2026, class S4 (accessed 30 September 2026)
- UniProt A0A0C5B5G6 (MOTS-c) and PubChem CID 146675088 (accessed 30 September 2026)
For laboratory research only. Clean Peptides products are not intended for use in humans or animals. This article provides general information and is not medical advice.
