Home / Research Library / Compound Research
MOTS-c is a 16-amino-acid peptide encoded not in the cell nucleus but in mitochondrial DNA, inside the gene for 12S ribosomal RNA. It was first described in 2015 by a team led from the University of Southern California, who reported that it acts mainly on skeletal muscle and affects insulin sensitivity in mice.1 Almost all the evidence on MOTS-c comes from cell and animal studies. We found no published controlled trial in which MOTS-c itself was given to people and clinical outcomes were reported.
This article explains what a mitochondrial-derived peptide is and what the key MOTS-c studies reported. It also covers what the limited human data show and how MOTS-c is classified in sport.
| Property | Detail |
|---|---|
| Full name | Mitochondrial open reading frame of the 12S rRNA-c1 |
| Class | Mitochondrial-derived peptide (MDP) |
| Sequence (one-letter) | MRWQEMGYIFYPRKLR (16 residues; PubChem lists H-MRWQEMGYIFYPRKLR-OH)2 |
| Molecular formula | C101H152N28O22S2 (PubChem)2 |
| Molar mass | 2174.6 g/mol (PubChem)2 |
| CAS number | 1627580-64-6 (PubChem)2 |
| Origin | Short open reading frame within the mitochondrial 12S rRNA gene; first reported 20151 |
| Approved medicines | None |
| WADA 2026 | Named in S4.4.1 as an activator of AMP-activated protein kinase (AMPK); prohibited at all times3 |
Mitochondria carry their own small circular genome, separate from the DNA in the nucleus. In textbook descriptions it encodes a handful of proteins used in energy production, plus the ribosomal and transfer RNAs mitochondria need to make them. The discovery of humanin, a signalling peptide encoded by a short open reading frame (sORF) in mitochondrial DNA, suggested that other hidden peptide-coding sequences might exist there.1 MOTS-c was the result of that search. The 2015 team reported a 51-base-pair sORF inside the 12S rRNA gene that yields a 16-residue peptide. Humanin and MOTS-c are now grouped together as mitochondrial-derived peptides.4
The idea behind this research is that mitochondria are not only energy producers but may also act as signalling units that communicate with the rest of the cell and body.1 Because it is detectable in several tissues and in circulation, MOTS-c has been dubbed a "mitochondrial hormone" or "mitokine" in the literature.5 The 2015 paper also framed the work around ageing. Its authors wrote that tissue and circulating levels of humanin and MOTS-c fall with age, and hypothesised that declining levels of these peptides may be related to age-related metabolic deterioration.1
In the original Cell Metabolism paper, Lee and colleagues identified skeletal muscle as the apparent primary target of MOTS-c. They reported that, in cells, it inhibits the folate cycle and the de novo purine synthesis linked to it, leading to activation of AMPK, a cellular energy sensor.1 In mice, MOTS-c was given by daily intraperitoneal injection in all in vivo experiments. The authors reported that it prevented age-dependent and high-fat-diet-induced insulin resistance, as well as diet-induced obesity, in their models. One arm used 0.5 mg/kg/day in outbred CD-1 mice on a 60% fat diet. These are mouse results under controlled conditions and have not been reproduced in human trials.
A 2018 follow-up from the same group reported that, under metabolic stress such as glucose restriction, MOTS-c moves from the cytoplasm into the nucleus of cultured cells in an AMPK-dependent way. There it influenced a broad range of genes, including those with antioxidant response elements, and interacted with the stress-responsive transcription factor NRF2.6 The authors presented this as evidence that the mitochondrial and nuclear genomes encode factors that cross-regulate each other.
A 2021 study in Nature Communications reported that MOTS-c treatment improved physical performance in young (2-month), middle-aged (12-month) and old (22-month) mice. Intermittent treatment started late in life (23.5 months) was reported to increase physical capacity and "healthspan" in mice.5 Several authors of these MOTS-c papers have disclosed consulting roles and shareholdings in CohBar, Inc.6,5
Human evidence on MOTS-c is observational or genetic. It measures the body's own (endogenous) peptide, or variants in the gene that encodes it, rather than testing administered MOTS-c.
In the same 2021 paper, 10 sedentary, healthy young men cycled on an ergometer while researchers sampled muscle and blood. MOTS-c in skeletal muscle rose 11.9-fold after exercise relative to pre-exercise values. Circulating levels rose 1.6-fold during exercise and 1.5-fold after it, returning to baseline after 4 hours of rest.5 This suggests MOTS-c is part of the normal exercise response, but a 10-person study cannot establish what the change does.
An Asian-specific mitochondrial DNA variant, m.1382A>C (rs111033358), changes the 14th amino acid of MOTS-c from lysine to glutamine (K14Q).7 A 2021 meta-analysis of three cohorts (27,527 people) found a higher prevalence of type 2 diabetes in men, but not women, carrying the C allele. In one cohort, the association appeared only in the least physically active men. In high-fat-fed male mice, standard MOTS-c improved glucose tolerance but the K14Q version did not. Earlier, Fuku and colleagues had proposed the same variant as one possible factor in exceptional longevity in Japan, while stressing that more research was needed.4
Two further studies looked at muscle. A 2022 study in Japanese participants examined the K14Q variant in 211 healthy individuals for muscle-fibre typing, and compared its frequency in 721 athletes and 873 controls. Carriers of the C allele had a higher proportion of fast-twitch (MHC-IIx) fibres. The allele was more frequent in sprint and power athletes (6.5%) than in controls (5.1%) or endurance athletes (2.9%).8 Separately, a 2023 preliminary study from Poland measured resting serum MOTS-c in 20 physically active volunteers. Levels correlated with jump power, force and muscle mass, but not with peak oxygen uptake.9 Both are association studies: they show that MOTS-c biology varies with muscle characteristics, not that giving MOTS-c changes them.
ClinicalTrials.gov lists a phase 2a, randomised, placebo-controlled trial of MOTS-c (NCT07505745, "MOTS-MET"). It is testing whether 12 weeks of treatment changes an oral-glucose-tolerance-test measure of insulin sensitivity in adults with prediabetes and overweight or obesity. The trial is sponsored by Hudson Biotech at a single site in Shenzhen, China, with an estimated 120 participants. Recruitment began in February 2026, and primary completion is estimated for February 2027.10 No results have been posted.
| Study | Model | Key reported finding |
|---|---|---|
| Lee et al., 2015 | Cells; mice | Muscle-targeted; folate-cycle inhibition and AMPK activation; prevented diet-induced insulin resistance in mice1 |
| Kim et al., 2018 | Cultured cells | Nuclear translocation under metabolic stress; regulation of antioxidant-response genes6 |
| Reynolds et al., 2021 | Mice; 10 young men (exercise) | Improved physical performance in mice of three ages; exercise raised endogenous MOTS-c in human muscle and blood5 |
| Zempo et al., 2021 | 3 human cohorts (27,527); mice | K14Q variant associated with type 2 diabetes in men; variant peptide lacked effect in mice7 |
| Kumagai et al., 2022 | Japanese individuals and athletes | K14Q carriers: more fast-twitch fibres; allele more common in sprint/power athletes8 |
| Domin et al., 2023 | 20 active adults (cross-sectional) | Serum MOTS-c correlated with jump power and muscle mass, not peak VO29 |
| NCT07505745 | Phase 2a RCT, prediabetes | Recruiting; no results10 |
The mechanism that recurs across the papers is AMPK activation. The 2015 study traced this to inhibition of the folate pathway, which leads to accumulation of the purine-synthesis intermediate AICAR, an AMPK activator.1 The 2018 study showed that AMPK is needed for MOTS-c's move into the nucleus under stress.6 The 2015 authors also pointed out parallels with the antifolate drug methotrexate, which likewise targets the same folate pathway, raises AICAR and activates AMPK.1 WADA's classification reflects this mechanism: the 2026 Prohibited List names MOTS-c in section S4.4.1 alongside AICAR and BAM15 as an activator of AMPK.3 Most of this mechanistic work comes from one research group and its collaborators, and independent replication in humans is limited.
Yes. MOTS-c is named in section S4.4.1 of the 2026 WADA Prohibited List. Substances in S4.4 are prohibited at all times, in and out of competition, and are non-Specified.3 The same subsection lists AICAR, and for 2026 WADA added BAM15 as a further example of an AMPK activator; its explanatory note says BAM15 had been found in supplements.11 Being named removes any ambiguity: there is no need to consider whether MOTS-c might fall under a catch-all clause. Sport Integrity Australia, Australia's national anti-doping organisation, includes MOTS-C in its list of common unapproved peptides that are prohibited in sport.12 Our article on peptides and the WADA Prohibited List sets out the sections for the other compounds on this site.
No medicine containing MOTS-c is approved. Sport Integrity Australia describes unapproved peptide products as goods that have not been included in the Australian Register of Therapeutic Goods.12 Titan Peptides supplies MOTS-c for laboratory research as a lyophilised 5 mg vial. It is intended for in vitro and animal work of the kind described above, not for human or veterinary use. In published cell work, for example, MOTS-c at 10 µM protected C2C12 mouse myoblasts during 48 hours of metabolic stress induced by glucose restriction.5 Short peptides containing methionine and tryptophan, as MOTS-c does, are sensitive to oxidation, so storage conditions matter; see our guide to storing lyophilised and reconstituted peptides. For how identity and purity of a peptide are established, see how HPLC and mass spectrometry test peptide purity.
MOTS-c is a short peptide of 16 amino acids that is encoded in mitochondrial DNA rather than in the cell nucleus. It was first described in 2015. In cell and mouse studies it acted mainly on skeletal muscle and activated AMPK, a cellular energy sensor. It is not an approved medicine, and its effects in people have not been established in clinical trials.
MOTS-c stands for mitochondrial open reading frame of the 12S rRNA-c. The name describes where it is encoded: a short open reading frame within the mitochondrial gene for 12S ribosomal RNA. It belongs to a group called mitochondrial-derived peptides, which also includes humanin.
Yes. The 2026 WADA Prohibited List names MOTS-c in section S4.4.1, metabolic modulators, as an activator of AMP-activated protein kinase, alongside AICAR. It is prohibited at all times, in and out of competition. Sport Integrity Australia also lists MOTS-C among common unapproved peptides that are prohibited in sport.
Not in a published controlled trial with clinical outcomes. Human studies so far have measured the body's own MOTS-c, for example its rise during exercise, or examined a genetic variant of it. A phase 2a placebo-controlled trial in adults with prediabetes (NCT07505745) began recruiting in 2026 and has not reported results.
It is a signalling peptide that has been detected in several tissues and in blood, and some researchers have dubbed it a mitochondrial hormone or mitokine. Formally it is classed as a mitochondrial-derived peptide. WADA does not list it under S2 with peptide hormones but under S4.4 as a metabolic modulator, specifically an AMPK activator.
Which peptides does the 2026 WADA Prohibited List name, in which section, and what does "not named" really mean? Includes GLP-1 drugs, retatrutide and Sport Integrity Australia.
A laboratory guide to storing lyophilised and reconstituted peptides: freezer temperatures, moisture, oxidation-prone residues, light, freeze–thaw cycles and adsorption to containers.
How reverse-phase HPLC and mass spectrometry are used to test peptide purity and identity, how to read a chromatogram and a mass spectrum, and what each method cannot tell you.
