MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) is a 16-amino-acid peptide encoded in mitochondrial DNA rather than in the cell nucleus. A University of Southern California group described it in 2015 as a signal that acts mainly on skeletal muscle and improves insulin sensitivity in mice. Researchers have described it as having “exercise mimetic” activity (Dieli-Conwright et al., Sci Rep 2021), and it is sold online as a “research peptide.”
The single most important fact is that no controlled trial of MOTS-c itself in people has published results. The only completed human study used CB4211, a modified analog made by CohBar, and its results exist only as company-reported topline data. Nearly everything else known comes from mice and cell culture. MOTS-c is not an approved drug, and the World Anti-Doping Agency (WADA) names it as a prohibited metabolic modulator.
This page summarizes what the published laboratory, animal and human observational studies and regulators report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Class | Mitochondrial-derived peptide (MDP); AMPK-activating metabolic regulator |
| Structure | 16 amino acids; C₁₀₁H₁₅₂N₂₈O₂₂S₂, 2,174.6 g/mol (PubChem) |
| Origin | Short open reading frame inside the mitochondrial 12S rRNA gene |
| Development stage | No approved product; one completed phase 1 study of an analog (CB4211); one phase 2 trial of MOTS-c registered in 2026 |
| Doses studied | Mice: 0.5–15 mg/kg/day by intraperitoneal injection. People: CB4211 25 mg once daily under the skin for 4 weeks |
| Half-life | No published human or animal plasma half-life found |
| US status | Not FDA-approved; not a controlled substance; FDA has flagged compounding safety concerns |
| WADA status | Prohibited at all times, class S4.4.1 (named explicitly) |
What it is
Mitochondria carry their own small genome. Within it, researchers have found short open reading frames (sORFs) that encode small signaling peptides. The first was humanin. MOTS-c was the next, found inside the gene for the mitochondrial 12S ribosomal RNA (Lee et al., Cell Metab 2015).
The 2015 paper reported that:
- the first 11 residues of MOTS-c are highly conserved across 14 species;
- MOTS-c is detectable in many mouse and rat tissues and in human and rodent plasma;
- experiments in cells stripped of mitochondrial DNA supported a mitochondrial, not nuclear, origin;
- fasting lowered MOTS-c in mouse skeletal muscle and plasma.
PubChem lists synthetic MOTS-c with the formula C₁₀₁H₁₅₂N₂₈O₂₂S₂ and a molecular weight of 2,174.6 g/mol (PubChem CID 146675088).
How it is thought to work
In cell culture, MOTS-c inhibits the folate-methionine cycle and the de novo purine synthesis pathway tied to it. This causes AICAR, an internal metabolite, to build up more than 20-fold in cells that overexpress the peptide. AICAR in turn activates AMP-activated protein kinase (AMPK), the cell’s main energy sensor (Lee et al., Cell Metab 2015). AICAR is also sold on its own as a research compound; see AICAR.
AMPK only partly explains the effects. Blocking AMPK in those cells cut the glycolytic effect of MOTS-c by 16–40%, depending on the method (Lee et al., Cell Metab 2015).
A 2018 study from the same lab found that, under metabolic stress such as glucose restriction, MOTS-c moves into the nucleus in an AMPK-dependent way. There it regulated many genes, including antioxidant-response genes, and interacted with the stress-response transcription factor NRF2 (Kim et al., Cell Metab 2018). These are cell-culture findings.
Pharmacokinetics
No pharmacokinetic study of MOTS-c in people has been published. We also found no published plasma half-life in animals.
CohBar’s phase 1a study of its analog CB4211 measured pharmacokinetics after single and multiple doses under the skin, but those data were not reported in the registry or in a peer-reviewed paper (NCT03998514). Because CB4211 is a modified molecule, its kinetics would not necessarily apply to MOTS-c.
A doping-control lab that built a mass spectrometry test for MOTS-c also identified four metabolites and two oxidation products formed in the test tube (Knoop et al., Rapid Commun Mass Spectrom 2019). The study did not report a half-life.
Regulatory status
- Approval. MOTS-c is not approved as a medicine by the FDA. Its only clinical-stage relative, CB4211, completed a phase 1a/1b study in 2021 (NCT03998514).
- New trial. A phase 2a randomized, placebo-controlled trial of MOTS-c itself began in February 2026. It plans to enroll 120 adults with prediabetes and overweight or obesity, giving a fixed daily dose under the skin for 12 weeks, with insulin sensitivity (Matsuda index) as the primary outcome. Primary completion is estimated for February 2027 (NCT07505745).
- FDA compounding review. MOTS-c was nominated for use in pharmacy compounding and placed in FDA’s “category 2,” the group of bulk substances that may present significant safety risks; the nomination was later withdrawn. FDA’s listing states that it “has not identified any human exposure data” on MOTS-c products by any route, and that compounded MOTS-c may carry a risk of immune reactions (immunogenicity) and peptide-related impurities (FDA).
- Controlled substances. MOTS-c is not named in the US Schedule III list that covers the anabolic steroids (21 CFR 1308.13).
- Sport. The WADA list names “mitochondrial open reading frame of the 12S rRNA-c (MOTS-c)” as an example of an AMPK activator under S4.4.1 Metabolic modulators. It is prohibited in and out of competition and is a non-Specified Substance, alongside AICAR and GW501516 (WADA 2026 Prohibited List). A validated mass spectrometry detection method for doping control was published in 2019 (Knoop et al., 2019).
What the research shows
Metabolism and insulin sensitivity in mice
The original paper treated mice with MOTS-c by intraperitoneal injection (Lee et al., Cell Metab 2015):
| Model | Dose and duration | Main finding |
|---|---|---|
| Mice | 5 mg/kg/day for 7 days | Better glucose tolerance |
| High-fat-diet mice (clamp study) | 5 mg/kg/day for 7 days | ≈30% higher glucose infusion rate, a measure of whole-body insulin sensitivity |
| Middle-aged mice | 5 mg/kg/day for 7 days | Insulin-stimulated glucose uptake in muscle restored to young levels |
| High-fat-diet mice | 0.5 mg/kg/day | Prevented diet-induced weight gain without changing food intake; no weight effect on a normal diet |
The authors concluded that skeletal muscle was the main target. MOTS-c levels in mouse muscle and blood fell with age.
Physical performance and aging in mice
A 2021 study from the same group focused on exercise capacity (Reynolds et al., Nat Commun 2021):
- Young mice given 15 mg/kg/day, but not 5 mg/kg/day, ran significantly longer and farther on a treadmill than controls. In a separate test, grip strength did not improve.
- Old mice (22 months) given 15 mg/kg/day for 2 weeks ran about 2-fold longer and 2.16-fold farther than untreated old mice.
- Late-life treatment started at about 24 months, 3 times a week, improved grip strength, stride length and a 60-second walking test near the end of life.
- Lifespan showed only a non-significant trend: median lifespan 6.4% and maximum lifespan 7.0% longer (P = 0.23 for the whole curve). The authors said larger cohorts are needed.
Many other rodent studies report protective effects in disease models, for example in diet-induced fatty liver disease (Lu et al., Cell Rep 2024) and pressure-overload heart failure (Zhong et al., J Cell Mol Med 2022). None of these uses has been tested in people.
Endogenous MOTS-c and exercise in people
Human studies so far measure the body’s own MOTS-c, not the effect of taking it:
| Study | Design | Finding |
|---|---|---|
| Reynolds et al. 2021 | 10 sedentary young men, one cycling session | Muscle MOTS-c rose 11.9-fold after exercise; plasma levels rose 1.6-fold during and 1.5-fold after, returning to baseline within 4 h |
| von Walden et al. 2021 | 30 adults randomized to endurance exercise, resistance exercise or control | Plasma MOTS-c showed only a non-significant trend upward after endurance exercise; levels were not related to fitness |
| Dieli-Conwright et al. 2021 | Secondary analysis of a 16-week exercise trial in 49 breast cancer survivors | MOTS-c rose with exercise in non-Hispanic White women but not in Hispanic women |
In observational studies, people with type 2 diabetes have lower circulating MOTS-c. A 2024 meta-analysis of 7 studies with 602 participants found lower levels in diabetes (SMD −0.89; 95% CI −1.12 to −0.65) but higher levels in obesity (SMD 0.51; 95% CI 0.21 to 0.81) (Zhou et al., Diabetol Metab Syndr 2024). These associations do not show that raising MOTS-c helps.
A caution on blood measurements. Most human studies measure MOTS-c with commercial or in-house ELISA kits. When a doping-control lab compared a commercial ELISA with a mass spectrometry method, the ELISA readings of 45.9–218.5 ng/mL in 20 healthy people could not be confirmed by mass spectrometry, whose detection limit was 100 pg/mL (Knoop et al., 2019). Absolute blood levels reported for MOTS-c should therefore be read with caution.
Genetic evidence
A MOTS-c variant found mainly in Northeast Asian people (m.1382A>C, which swaps one amino acid, K14Q) was proposed as a possible factor in Japanese longevity (Fuku et al., Aging Cell 2015). A later meta-analysis of three cohorts with 27,527 people linked the same variant to a higher prevalence of type 2 diabetes in men but not women, especially in men with low physical activity. In mice, the variant peptide lost the weight and glucose benefits of normal MOTS-c (Zempo et al., Aging 2021).
The analog CB4211 in people
CohBar developed CB4211, which it describes as an “improved analog” of MOTS-c, for fatty liver disease and obesity (CohBar 10-K, 2022). Its phase 1a/1b study enrolled 88 people: healthy non-obese adults in the dose-escalation parts, then obese adults with nonalcoholic fatty liver disease (NAFLD) given daily injections or placebo for 28 days (NCT03998514).
According to the company’s topline data:
| Measure after 4 weeks | CB4211 25 mg daily (n = 11) | Placebo (n = 9) |
|---|---|---|
| ALT (liver enzyme) | −21% | +4% (difference significant) |
| AST (liver enzyme) | −28% | −11% (difference significant) |
| Glucose | −6% | 0% (difference significant) |
| Liver fat by MRI, absolute change | −5.03 points | −4.88 points |
| Share with 30% or greater relative drop in liver fat | 36% | 33% |
Liver fat, the main imaging outcome, fell about equally on drug and placebo. Body weight showed only a trend. These results come from a company filing, involve 20 people, and have not been published in a peer-reviewed journal.
Side effects and risks
No human safety data for MOTS-c itself
FDA states it has found no human exposure data for MOTS-c by any route (FDA). Its side effects, safe dose range and long-term effects in people are unknown.
What the analog study showed
In the CB4211 study, the phase 1a participants developed mild but persistent injection-site reactions, described as painless bumps under the skin. CohBar changed the formulation partway through, after which these were no longer seen. The company reported no serious adverse events in the phase 1b part (CohBar 10-K, 2022).
Product quality and immune reactions
FDA’s compounding review flagged two concerns for compounded MOTS-c given by certain routes: possible immunogenicity (the body making antibodies or other immune responses against the peptide) and peptide-related impurities that are hard to characterize (FDA). Products sold as “research peptides” are not made to drug manufacturing standards, so their identity, purity and sterility are not verified.
Anti-doping
Because MOTS-c is named on the WADA list and a detection method exists, athletes in tested sports face sanctions for its use (WADA 2026 Prohibited List).
Key takeaways
- A peptide encoded by mitochondrial DNA. MOTS-c is 16 amino acids long, comes from the 12S rRNA gene, and is a relative of humanin.
- Animal data are promising but limited. In mice it improved insulin sensitivity, prevented diet-induced weight gain and roughly doubled running time in old animals. Lifespan gains were not significant.
- No published human trial of MOTS-c itself. The only clinical data come from a 20-person, company-reported study of the analog CB4211, which lowered liver enzymes but not liver fat compared with placebo.
- Human studies only measure natural levels. Exercise raises muscle and blood MOTS-c, and levels are lower in type 2 diabetes, but ELISA-based measurements are unreliable.
- Unknown safety and quality. FDA found no human exposure data and flagged immunogenicity and impurity risks for compounded MOTS-c.
- Banned in sport. WADA names MOTS-c under S4.4.1 metabolic modulators, prohibited at all times.
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 Metab. 2015;21(3):443–454. PubMed.
- 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. PubMed.
- 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. Nat Commun. 2021;12(1):470. PubMed.
- von Walden F, Fernandez-Gonzalo R, Norrbom J, et al. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans. J Appl Physiol (1985). 2021;131(3):1035–1042. PubMed.
- Dieli-Conwright CM, Sami N, Norris MK, et al. Effect of aerobic and resistance exercise on the mitochondrial peptide MOTS-c in Hispanic and Non-Hispanic White breast cancer survivors. Sci Rep. 2021;11(1):16916. PubMed.
- Zhou Q, Yin S, Lei X, et al. The correlation between mitochondrial derived peptide (MDP) and metabolic states: a systematic review and meta-analysis. Diabetol Metab Syndr. 2024;16(1):200. PubMed.
- Fuku N, Pareja-Galeano H, Zempo H, et al. The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity? Aging Cell. 2015;14(6):921–923. PubMed.
- 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. PubMed.
- 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 Commun Mass Spectrom. 2019;33(4):371–380. PubMed.
- National Center for Biotechnology Information. MOTS-c, PubChem Compound CID 146675088. PubChem.
- CohBar, Inc. A Phase 1a/1b Study of CB4211 in Healthy Non-obese Subjects and Subjects With Nonalcoholic Fatty Liver Disease. ClinicalTrials.gov identifier NCT03998514. ClinicalTrials.gov.
- CohBar, Inc. Annual report (Form 10-K) for the fiscal year ended December 31, 2021. Filed March 29, 2022. SEC.
- Hudson Biotech. MOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/Obesity. ClinicalTrials.gov identifier NCT07505745. ClinicalTrials.gov.
- 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.
- World Anti-Doping Agency. World Anti-Doping Code International Standard: Prohibited List 2026. WADA 2026 Prohibited List.
- Lu H, Fan L, Zhang W, et al. The mitochondrial genome-encoded peptide MOTS-c interacts with Bcl-2 to alleviate nonalcoholic steatohepatitis progression. Cell Rep. 2024;43(1):113587. PubMed.
- Zhong P, Peng J, Hu Y, et al. Mitochondrial derived peptide MOTS-c prevents the development of heart failure under pressure overload conditions in mice. J Cell Mol Med. 2022;26(21):5369–5378. PubMed.
- Code of Federal Regulations. 21 CFR 1308.13, Schedule III. eCFR.