Monograph in Mitochondria-targeted peptides
MOTS-c
A 16-residue peptide encoded inside mitochondrial DNA, discovered in 2015. In mice it improves insulin sensitivity and physical capacity; in people, it has so far only been measured, not tested.
Also called Mitochondrial open reading frame of the 12S rRNA-c · MOTSc
Best evidence: Preclinical only
Effects of giving MOTS-c are shown only in cells and mice. Human studies measure naturally occurring levels; a phase 2 trial is recruiting.
Not FDA-approved · FDA compounding nomination withdrawn
Residue Editorial Team · updated
What is MOTS-c?
MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) is a 16-amino-acid peptide encoded in the mitochondrial genome. In mice, it prevented diet-induced obesity and age- and diet-related insulin resistance1PubMedThe mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Lee C et al. Cell Metab. 2015. and improved physical performance at all ages2PubMedMOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Reynolds JC et al. Nat Commun. 2021.. Human studies so far measure natural blood levels3PubMedPlasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. Cataldo LR et al. J Investig Med. 2018.; FDA has identified no human exposure data for MOTS-c products4FDACertain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks. U.S. FDA, content current as of 04/22/2026..
Key findings
- MOTS-c is encoded by a short open reading frame within the mitochondrial 12S rRNA gene; its primary target appears to be skeletal muscle, where it inhibits the folate cycle and activates AMPK1.
- MOTS-c treatment prevented age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity in mice1.
- It enhanced physical performance in young, middle-aged and old mice; treatment started at 23.5 months increased physical capacity and healthspan2.
- In humans, exercise induced MOTS-c expression in muscle and blood2; plasma levels were similar in 10 lean and 10 obese people3.
- FDA lists MOTs-C among withdrawn compounding nominations, with no identified human exposure data and possible significant immunogenicity risk4.
What is MOTS-c, chemically?
| PubChem CID | 146675088 “Mots-c” |
|---|---|
| Formula | C101H152N28O22S2 |
| Molecular weight | 2,174.6 g/mol |
| CAS (as listed) | 1627580-64-6 |
| FDA UNII | A5CV6JFB78 |
| InChIKey | WYTHCOXVWRKRAH-LOKRTKBUSA-N |
| Length | 16 residues |
| Mechanism | Mitochondrial-derived peptide; folate-cycle inhibition and AMPK activation in muscle |
- Hydrophobic
- Polar
- Basic (+)
- Acidic (−)
- Gly / Pro / Cys
What is MOTS-c?
Most proteins are encoded in the cell nucleus, but mitochondria carry their own small genome. In 2015, researchers reported a short open reading frame within the mitochondrial 12S rRNA gene encoding a 16-amino-acid peptide they named MOTS-c1. PubChem's record gives its sequence as Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg (Figure 1)5PubChemPubChem compound record: Mots-c. C101H152N28O22S2 · MW 2174.6 g/mol.. A review describes MOTS-c moving into the nucleus during metabolic stress to direct nuclear gene expression6PubMedMOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. Zheng Y et al. Front Endocrinol (Lausanne). 2023..
How is MOTS-c thought to work?
The discovery paper identified skeletal muscle as the primary target. In cells, MOTS-c inhibits the folate cycle and the de novo purine biosynthesis linked to it, which activates AMPK, a central energy sensor1. Later work found it reduces myostatin and muscle-atrophy signaling through AKT, FOXO1, mTORC2, PTEN and CK27PubMedMOTS-c reduces myostatin and muscle atrophy signaling. Kumagai H et al. Am J Physiol Endocrinol Metab. 2021..
What have studies found?
Metabolism in mice. MOTS-c treatment prevented both age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity1.
Aging and exercise in mice. A 2021 Nature Communications study found MOTS-c significantly enhanced physical performance in young (2 months), middle-aged (12 months) and old (22 months) mice, and that intermittent treatment three times a week started in late life (23.5 months) increased physical capacity and healthspan2.
Muscle. Plasma MOTS-c correlated inversely with myostatin in human subjects; MOTS-c prevented palmitic-acid-induced atrophy in muscle cells and lowered plasma myostatin in diet-induced obese mice7.
Humans. Exercise induced endogenous MOTS-c in human skeletal muscle and circulation2. In 10 lean and 10 obese adults, plasma MOTS-c was similar (0.48 versus 0.52 ng/mL) but correlated with insulin-resistance indices, mainly in lean individuals3. A 2023 review concluded that no effective method of applying MOTS-c in the clinic had yet been developed6. At our fetch, ClinicalTrials.gov listed a recruiting phase 2 study in prediabetes with overweight or obesity8TrialMOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/Obesity. Hudson Biotech · PHASE2 · recruiting..
Is MOTS-c FDA-approved?
| Record | Status | Source |
|---|---|---|
| FDA approval | No approved application Drugs@FDA returned no application for “MOTS-c”. | openFDA |
| Compounding: nominated, then withdrawn MOTs-C | Withdrawn nomination FDA still lists its safety concerns: “Compounded drugs containing MOTs-C may pose significant risk for immunogenicity for certain routes of administration and may have complexities with regard to peptide-related impurities and API characterization. FDA has not identified any human exposure data on drug products containing MOTs-C administered via any route of administration. FDA lacks important information regarding any safety issues raised by MOTs-C,…” | 4 |
FDA's entry for "MOTs-C" warns of possibly significant immunogenicity risk and complexities in impurity and API characterization. It states FDA has not identified any human exposure data on products containing MOTS-c by any route and lacks important information about whether it would cause harm in humans4.
What is still unknown?
- Human pharmacology and safety of administered MOTS-c are unknown; the registered phase 2 trial may provide the first data8.
- Translation of mouse aging and metabolism effects to people.
What effects has MOTS-c shown, by body system?
Each row is graded separately using the Residue evidence scale: a compound can carry an A for one use and a D for another.
| System | What was observed | Grade |
|---|---|---|
| Insulin sensitivity (mice) | Prevented diet- and age-induced insulin resistance1. | D |
| Physical capacity (mice) | Improved performance and healthspan, including late-life treatment2. | D |
| Muscle atrophy | Lowered plasma myostatin in obese mice and prevented myotube atrophy in vitro7. | D |
| Human physiology | Endogenous levels rise with exercise2 and correlate with insulin-sensitivity indices in lean people3 — observational only. | D |
How much research is there on MOTS-c?
| Phase | Studies | Breakdown |
|---|---|---|
| Phase 2 | 1 | 0 completed, 1 active or recruiting, 0 stopped, 0 other |
| Not applicable | 1 | 0 completed, 1 active or recruiting, 0 stopped, 0 other |
| Observational | 3 | 0 completed, 2 active or recruiting, 0 stopped, 1 other |
Compare and continue
- Elamipretide (SS-31) vs MOTS-cComparison
- ElamipretideMitochondria-targeted peptides
- EpitalonRegulatory peptides
- SemaglutideIncretin & amylin agonists
Questions readers ask
What is MOTS-c?
A 16-amino-acid peptide encoded by a short open reading frame in the mitochondrial 12S rRNA gene, described in 2015 as a regulator of insulin sensitivity and metabolic homeostasis1.
Has MOTS-c been tested in humans?
Not as a treatment in any published study we found. Human research has measured natural levels — rising with exercise2 and relating to insulin sensitivity in lean people3. A phase 2 trial in prediabetes is registered as recruiting8.
Is MOTS-c FDA-approved?
No. FDA lists MOTs-C among withdrawn compounding nominations and says it has not identified any human exposure data and lacks information on whether it would cause harm4.
How is MOTS-c different from SS-31 (elamipretide)?
MOTS-c is a naturally encoded mitochondrial peptide with mouse data only1; elamipretide is a synthetic cardiolipin-binding peptide with randomized trials and an FDA accelerated approval for Barth syndrome9.
Does MOTS-c decline with age?
A 2023 review states that plasma MOTS-c levels decrease with age6.
References
Every source below was retrieved from its official API or page and cached on the data-edition date. Numbers match the margin notes.
- 1 PubMed 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. PMID 25738459; doi:10.1016/j.cmet.2015.02.009.
- 2 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. PMID 33473109; doi:10.1038/s41467-020-20790-0.
- 3 PubMed Cataldo LR, Fernández-Verdejo R, Santos JL, et al. Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. J Investig Med 2018. PMID 29593067; doi:10.1136/jim-2017-000681.
- 4 FDA Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks. U.S. FDA, content current as of 04/22/2026.
- 5 PubChem PubChem compound record: Mots-c. C101H152N28O22S2 · MW 2174.6 g/mol.
- 6 PubMed Zheng Y, Wei Z, Wang T. MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. Front Endocrinol (Lausanne) 2023. PMID 36761202; doi:10.3389/fendo.2023.1120533.
- 7 PubMed Kumagai H, Coelho AR, Wan J, et al. MOTS-c reduces myostatin and muscle atrophy signaling. Am J Physiol Endocrinol Metab 2021. PMID 33554779; doi:10.1152/ajpendo.00275.2020.
- 8 ClinicalTrials.gov MOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/Obesity. Hudson Biotech · PHASE2 · recruiting.
- 9 FDA FORZINITY prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2025-12-10.