# MOTS-c
**MOTS-c** (mitochondrial open reading frame of the 12S rRNA type-c) is a 16-amino-acid signaling peptide encoded within the mitochondrial genome, in the short open reading frame of the 12S ribosomal RNA gene [MT-RNR1](https://www.edgepedia.org/mt-rnr1), rather than in the cell's nuclear DNA.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7750512/) It belongs to the mitochondrial-derived peptides (MDPs), a small family that also includes humanin and the six small humanin-like peptides (SHLP1-6), and it has been studied for roles in metabolism, exercise adaptation, and aging.[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7750512/) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC9570330/)
| Key fact | Detail |
|---|---|
| Identity | 16-amino-acid peptide encoded by the mitochondrial 12S rRNA gene (MT-RNR1); molecular weight 2174.6 g/mol; CAS 1627580-64-6[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC7750512/) • [3](https://motscco.com/monograph) |
| Discovery | Identified in 2015, after humanin in 2001; shown to be of mitochondrial, not nuclear, DNA origin[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC9570330/) |
| Exercise response | In 10 sedentary healthy young men, skeletal muscle MOTS-c rose 11.9-fold after stationary cycling; plasma rose 1.6-fold during and 1.5-fold after exercise[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7817689/) |
| Mouse effects | Daily treatment improved treadmill performance in young, middle-aged, and old mice; old mice ran 2-fold longer and 2.16-fold farther[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7817689/) |
| Mechanism | Inhibits the folate cycle and de novo purine synthesis, activating AMPK; under metabolic stress it translocates to the nucleus and modulates adaptive gene expression[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC9570330/) • [5](https://mdpi-res.com/d_attachment/metabolites/metabolites-13-00125/article_deploy/metabolites-13-00125.pdf) |
| Human clinical status | No completed randomized controlled trial of administered MOTS-c; a 120-person Phase 2a metabolic trial has been recruiting, with no posted results[6](https://lifesco.re/edge/does-mots-c-have-human-metabolic-evidence/) |
## Discovery and molecular identity
MOTS-c was identified in 2015, fourteen years after the discovery of humanin in 2001, as a new mitochondrial-derived peptide.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC9570330/) Human mitochondrial DNA is a 16.6 kb double-stranded molecule encoding 13 proteins, two rRNAs, and 22 tRNAs, and MOTS-c is transcribed from a short open reading frame inside the 12S rRNA gene.[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC9854231/) Investigators initially considered whether the peptide might come from a nuclear mitochondrial DNA transfer segment (a NUMT), but it was shown to be completely homologous to the mitochondrial genome itself.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC9570330/)
The peptide's sequence is H-Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg-OH.[3](https://motscco.com/monograph) It is detected in multiple tissues, including skeletal muscle, and in circulation, and its expression is age-dependent, which has led to descriptions of it as a "mitochondrial hormone" or "mitokine".[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7817689/)
## Exercise response in humans
**Exercise raises endogenous MOTS-c.** In a study of 10 sedentary healthy young men (mean age 24.5 years, BMI 24.1) who exercised on a stationary bicycle, western blotting showed skeletal muscle MOTS-c increased 11.9-fold after exercise and remained elevated after a 4-hour rest, with a trend back toward baseline.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7817689/) ELISA measurements showed circulating MOTS-c rose 1.6-fold during and 1.5-fold after exercise, returning to baseline after 4 hours of rest.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7817689/) A separate trial comparing acute endurance exercise (45 minutes of cycling at 70% of estimated VO2max) with resistance exercise found that plasma levels of mitochondrial-derived peptides were not related to fitness status, though acute endurance exercise increased circulating levels.[8](https://pubmed.ncbi.nlm.nih.gov/34351816/)
A 16-week supervised aerobic and resistance exercise program versus usual care in physically inactive breast cancer survivors measured plasma MOTS-c as an outcome; levels rose significantly in non-Hispanic White participants but not in Hispanic participants, in whom the peptide was instead associated with reduced fat mass and HOMA-IR.[3](https://motscco.com/monograph) • [9](https://pmc.ncbi.nlm.nih.gov/articles/PMC8376922/)
## Animal evidence
**Physical performance.** In mice, MOTS-c treatment significantly improved physical performance in young (2 months), middle-aged (12 months), and old (22 months) animals.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7817689/) Daily treatment for two weeks at 15 mg/kg by intraperitoneal injection increased treadmill running time and distance; old mice ran 2-fold longer and 2.16-fold farther than untreated controls, and 17% of treated old mice reached the highest sprint stage while none of the untreated group did.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7817689/) In young mice on a high-fat diet, the higher of two doses (5 and 15 mg/kg/day) enabled 100% of mice to reach the final sprint stage, versus 16.6% on the lower dose and in controls.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7817689/)
**Metabolic effects.** Earlier work from the same group reported that systemic MOTS-c treatment reversed diet-induced obesity and diet- and age-dependent insulin resistance in mice.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7817689/) Metabolomic analysis showed MOTS-c regulated glycolysis, the pentose phosphate pathway, and amino acid metabolism in skeletal muscle, and the skeletal muscles of non-exercised mice showed no significant alterations, suggesting the peptide induces an adaptive metabolic response to exercise rather than a resting-state change.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7817689/) Late-life treatment initiated at 23.5 months of age, three times per week, increased physical capacity and healthspan in mice.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7817689/) Exogenous MOTS-c also stimulates thermogenesis in subcutaneous white adipose tissue, contributing to energy expenditure and anti-obesity effects in animal models.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC9171157/)
## Mechanism
MOTS-c's best-characterized metabolic mechanism is inhibition of the folate cycle and de novo purine biosynthesis in skeletal muscle cells, which activates AMPK ([AMP-activated protein kinase](https://www.edgepedia.org/amp-activated-protein-kinase)), a cellular energy sensor that controls glycolysis and mitochondrial function.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC9570330/) • [5](https://mdpi-res.com/d_attachment/metabolites/metabolites-13-00125/article_deploy/metabolites-13-00125.pdf) Under metabolic stress, the peptide translocates from the cytoplasm to the nucleus, where it modulates adaptive nuclear gene expression, a mitochondria-to-nucleus signaling route known as retrograde signaling.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC9570330/) In C2C12 muscle cells, MOTS-c enhanced adaptation to metabolic stress in an HSF1-dependent manner, implicating the heat-shock response.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC7817689/) Although exercise promotes MOTS-c expression, the exact molecular mechanism of that induction is not clear.[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC9854231/)
## State of the human evidence
The human literature consists almost entirely of studies measuring naturally circulating MOTS-c during exercise, heat exposure, metformin administration, or in disease cohorts; published trial-type records do not administer the peptide to participants.[6](https://lifesco.re/edge/does-mots-c-have-human-metabolic-evidence/) • [11](https://peptideamerica.org/evidence/mots-c-evidence) For nominated uses including insulin resistance, obesity, muscle and fat metabolism, and longevity, the FDA did not identify clinical studies administering MOTS-c substances to humans.[6](https://lifesco.re/edge/does-mots-c-have-human-metabolic-evidence/) A randomized, double-blind, placebo-controlled Phase 2a trial of subcutaneous MOTS-c in adults with prediabetes and overweight or obesity, planned for 120 participants, has been recruiting with no efficacy results posted.[6](https://lifesco.re/edge/does-mots-c-have-human-metabolic-evidence/) • [12](https://www.whichpeps.com/compound/mots-c/) An analog, CB4211, has been in early phase 1 trials.[13](https://e-space.mmu.ac.uk/641536/1/pharmaceuticals-18-01222.pdf)
MOTS-c holds no marketing authorization for any therapeutic use and is supplied only as a research compound.[14](https://compoundevidence.com/monographs/mots-c/) Reviews note that despite considerable therapeutic potential in preclinical models, effective clinical application has not yet been established.[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC9854231/)
## References
1. [Mitochondria-derived peptides in energy metabolism, American Journal of Physiology-Endocrinology and Metabolism](https://pmc.ncbi.nlm.nih.gov/articles/PMC7750512/)
2. [MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases, IJMS](https://pmc.ncbi.nlm.nih.gov/articles/PMC9570330/)
3. [MOTS-c Monograph: Evidence, Dosing, Safety, MOTS-c Co](https://motscco.com/monograph)
4. [MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis, Nature Communications (2021)](https://pmc.ncbi.nlm.nih.gov/articles/PMC7817689/)
5. [MOTS-c Functionally Prevents Metabolic Disorders, Metabolites](https://mdpi-res.com/d_attachment/metabolites/metabolites-13-00125/article_deploy/metabolites-13-00125.pdf)
6. [Does MOTS-c have human metabolic evidence?, lifesco.re](https://lifesco.re/edge/does-mots-c-have-human-metabolic-evidence/)
7. [Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC9854231/)
8. [Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans, PubMed](https://pubmed.ncbi.nlm.nih.gov/34351816/)
9. [Effect of aerobic and resistance exercise on the mitochondrial peptide MOTS-c in Hispanic and Non-Hispanic White breast cancer survivors, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC8376922/)
10. [Exercise, Mitohormesis, and Mitochondrial ORF of the 12S rRNA Type-C (MOTS-c), PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC9171157/)
11. [MOTS-c: Mitochondria, No Human Outcomes, Peptide America](https://peptideamerica.org/evidence/mots-c-evidence)
12. [MOTS-c evidence, WhichPeps](https://www.whichpeps.com/compound/mots-c/)
13. [MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation (Pharmaceuticals, MMU repository)](https://e-space.mmu.ac.uk/641536/1/pharmaceuticals-18-01222.pdf)
14. [MOTS-c compound monograph, Compound Evidence Institute](https://compoundevidence.com/monographs/mots-c/)
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*Topic: Encyclopedia › Life and health › Biological foundations › Genetics and genomic reference › Human gene and locus records*
*Initially written Sep 17, 2026 · Reviewed: Oct 21, 2026 · Edited: Oct 11, 2026; Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
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License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license