By Sequora Research Team · Updated October 2026
What is MOTS-c? It is a 16-amino-acid peptide encoded inside mitochondrial DNA, within the gene for the 12S ribosomal RNA. It was first described in 2015 and is studied as a signal that links mitochondria to cell metabolism [R1].
This monograph covers the MOTS-c peptide itself: its sequence and identifiers, where it comes from, what the key studies measured, and its regulatory status. For a side-by-side with another mitochondria-focused compound, see our MOTS-c vs SS-31 comparison. For the wider class, read what mitochondrial peptides are.
MOTS-c at a glance: sequence and identifiers
The name stands for “mitochondrial open reading frame of the 12S rRNA-c.” That full name is also the wording used by the World Anti-Doping Agency (WADA) [R4]. The table below lists the core identifiers, checked against PubChem [R5].
| Property | Value |
|---|---|
| Sequence (one-letter) | MRWQEMGYIFYPRKLR |
| Sequence (three-letter) | Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg |
| Length | 16 amino acids |
| Molecular formula | C101H152N28O22S2 |
| Molecular weight | 2174.6 g/mol |
| CAS number | 1627580-64-6 |
| PubChem CID | 146675088 |
| Origin | Short open reading frame in the mitochondrial 12S rRNA gene |
| First described | Lee et al., Cell Metabolism, 2015 |
The sequence holds two methionines, which is why the formula contains two sulfur atoms. It also carries several basic residues (three arginines and one lysine), so the peptide has a net positive charge near neutral pH.
Where MOTS-c comes from
Most proteins in a cell are encoded by nuclear DNA. Mitochondria keep a small genome of their own. It encodes ribosomal RNAs, transfer RNAs and a short list of proteins.
Lee and colleagues searched that genome for short open reading frames. They identified one inside the 12S rRNA gene that encodes a 16-residue peptide, which they named MOTS-c [R1]. This placed MOTS-c among the “mitochondrial-derived peptides,” a small group of peptides encoded by mitochondrial DNA. Our mitochondrial peptides overview covers the rest of that group.
Naming and spelling
The peptide is written several ways in papers and searches: MOTS-c, MOTSc and “mots c.” All refer to the same 16-residue sequence. When comparing suppliers or papers, the sequence and CAS number are more reliable than the name [R5].
The discovery mattered for a basic reason. It suggested that mitochondria do not only receive instructions from the nucleus. They may also send peptide signals of their own.
What does MOTS-c do? What studies have measured
Searches for “what does MOTS-c do” usually expect a list of effects. A more accurate answer is a list of what published studies measured, in which models. Three papers from the same research group form the core of the literature.
2015: folate cycle, AMPK and skeletal muscle (cells and mice)
In the first paper, Lee et al. reported that MOTS-c inhibited the folate cycle and the de novo purine biosynthesis linked to it [R1]. They connected this to activation of AMP-activated protein kinase (AMPK), a cellular energy sensor.
The authors identified skeletal muscle as a primary target tissue. In mice, they reported that MOTS-c administration prevented diet-induced obesity and insulin resistance on a high-fat diet. They also reported effects on age-related insulin resistance in mice [R1]. These are mouse findings and have not been shown in people.
2018: movement into the nucleus under metabolic stress (cells)
Kim et al. followed MOTS-c inside cells exposed to metabolic stress, such as glucose restriction. They reported that MOTS-c moved into the nucleus, and that this translocation depended on AMPK [R2].
Once in the nucleus, MOTS-c was associated with changes in nuclear gene expression. The genes included those carrying antioxidant response elements (ARE). The authors also reported interaction with stress-responsive transcription factors, including NRF2 [R2]. They framed this as evidence that the mitochondrial and nuclear genomes regulate each other.
2021: exercise and aging (human samples and mice)
Reynolds et al. described MOTS-c as an exercise-induced, mitochondrial-encoded peptide [R3]. In human volunteers, they measured endogenous MOTS-c in skeletal muscle and in circulation. Both levels were higher after exercise.
In mice, the same group measured physical performance in young, middle-aged and old animals given MOTS-c. They also tested intermittent administration started late in life and reported higher physical capacity measures in those mice [R3]. The human data in this paper are measurements of the body’s own MOTS-c with exercise. They are not trials of supplied MOTS-c.
Summary of the key studies
| Study | Model | What was measured |
|---|---|---|
| Lee et al., 2015 [R1] | Cells; mice | Folate cycle and purine synthesis, AMPK activation, skeletal muscle targeting, diet-induced obesity and insulin resistance in mice |
| Kim et al., 2018 [R2] | Cells under metabolic stress | AMPK-dependent nuclear translocation, ARE-linked gene expression, NRF2 interaction |
| Reynolds et al., 2021 [R3] | Human muscle and plasma; mice of several ages | Endogenous MOTS-c with exercise in people; physical capacity measures in mice |
Note what this table does not contain. There are no completed, peer-reviewed clinical trials of supplied MOTS-c in this core literature. Claims online that go beyond these models are extrapolation.
Regulatory status: FDA and WADA
FDA
MOTS-c is not an FDA-approved drug. It was nominated as a bulk substance for pharmacy compounding, and FDA’s compounding safety page (updated April 2026) records the agency’s assessment. FDA wrote that it had not identified any human exposure data on drug products containing MOTS-c [R6].
The same FDA page flagged possible immunogenicity risk for some routes of exposure. It also noted complexities around peptide-related impurities and characterization [R6]. The nomination was later withdrawn by the nominators. That is a separate matter from approval.
WADA
MOTS-c is prohibited in sport. The WADA 2026 Prohibited List names it in section S4.4.1, under metabolic modulators [R4]. It appears there as an example of an AMPK activator, listed alongside AICAR.
That placement matches the 2015 mechanism work, which linked MOTS-c to AMPK activation [R1]. Athletes subject to the World Anti-Doping Code should check the current list with their anti-doping organization.
MOTS-c for laboratory research
Sequora supplies MOTS-c (40 mg) for in vitro and laboratory research only. It is part of our mitochondrial peptides collection. We do not provide dosing, administration or use guidance of any kind.
Each vial is lyophilized, sealed and labelled with a batch code. Each batch is third-party tested by HPLC for purity and by mass spectrometry for identity. A certificate of analysis (COA) for any batch is available by email at research@sequorapeptides.com.
For a 16-residue peptide like MOTS-c, the mass spectrometry identity reading should match the expected mass near 2174.6 Da. Our guide on how to read a peptide COA explains what to check. Orders ship to the US and Canada.
MOTS-c FAQ
What is the MOTS-c peptide made of?
It is a chain of 16 amino acids with the sequence MRWQEMGYIFYPRKLR. Its formula is C101H152N28O22S2 and its molecular weight is about 2174.6 g/mol [R5].
Where is MOTS-c encoded?
It is encoded by a short open reading frame inside the 12S rRNA gene of mitochondrial DNA. Lee et al. first described it in 2015 [R1].
Is MOTS-c naturally present in the body?
Yes. Reynolds et al. measured endogenous MOTS-c in human skeletal muscle and plasma, with higher levels after exercise [R3].
Is MOTS-c FDA approved?
No. In 2026, FDA stated it had not identified human exposure data on drug products containing MOTS-c [R6].
Is MOTS-c banned by WADA?
Yes. The 2026 Prohibited List names MOTS-c under S4.4.1, as an AMPK activator within metabolic modulators [R4].
How is MOTS-c different from SS-31?
MOTS-c is a natural 16-residue peptide encoded by mitochondrial DNA. SS-31 is a synthetic tetrapeptide designed to reach the inner mitochondrial membrane. See what SS-31 is for its monograph.
References
- Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443–454. doi:10.1016/j.cmet.2015.02.009. PMID 25738459.
- 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 Metab. 2018;28(3):516–524.e7. doi:10.1016/j.cmet.2018.06.008. PMID 29983246.
- Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, Lu R, Cohen P, Graham NA, Benayoun BA, Merry TL, Lee C. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12:470. doi:10.1038/s41467-020-20790-0.
- World Anti-Doping Agency. The Prohibited List (2026), S4.4 Metabolic modulators. wada-ama.org/en/prohibited-list.
- National Center for Biotechnology Information. PubChem Compound Summary for CID 146675088, MOTS-c. pubchem.ncbi.nlm.nih.gov/compound/146675088.
- U.S. Food and Drug Administration. Certain bulk drug substances for use in compounding that may present significant safety risks (content current as of April 22, 2026). fda.gov.
For laboratory research use only. Not for human or veterinary use.