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A 16-residue peptide encoded inside the mitochondrial 12S rRNA gene that reduced obesity and insulin resistance in mice and is now in its first phase 2 trial.
Also known as: mitochondrial ORF of the 12S rRNA type-c · MOTS-c (human)
Part of the Metabolic & GLP-1 peptides cluster
Overview
MOTS-c is a 16-amino-acid peptide (MRWQEMGYIFYPRKLR; C101H152N28O22S2, ≈2,175 Da) encoded by a short open reading frame inside the mitochondrial 12S rRNA gene. Discovered in 2015, it promoted metabolic homeostasis and reduced obesity and insulin resistance in mice, and translocates to the nucleus under metabolic stress to regulate nuclear genes. Plasma levels decline with age. It is a research compound with no approval; its first phase 2 trial, in prediabetes, was recruiting in 2026.
Source & context
Biological / chemical source: Encoded by mitochondrial DNA (MT-RNR1 region)
Primary research or clinical context: Research compound — not approved anywhere. First phase 2 trial (insulin sensitivity in prediabetes) recruiting as of 2026.
What MOTS-c is
MOTS-c stands for mitochondrial open reading frame of the 12S rRNA type-c. It is a 16-amino-acid peptide translated from a short open reading frame hidden inside the gene for the mitochondrial 12S ribosomal RNA — a discovery reported in 2015 by Changhan Lee, Pinchas Cohen and colleagues, who were following up the earlier finding that another mitochondrial sORF encodes the signalling peptide humanin (Lee et al., Cell Metabolism 2015). Its sequence is MRWQEMGYIFYPRKLR, its formula C101H152N28O22S2 and its mass about 2,175 Da. It is found across tissues and in plasma, and plasma levels fall with age (Zheng et al., Frontiers in Endocrinology 2023).
What the mouse studies showed
In the discovery paper, MOTS-c promoted metabolic homeostasis and reduced obesity and insulin resistance in mice, acting on skeletal-muscle metabolism (Lee et al., 2015). Later work showed that under metabolic stress MOTS-c translocates from the cytoplasm to the nucleus, where it regulates nuclear gene expression in response to that stress (Kim et al., Cell Metabolism 2018) — an unusual mechanism for a mitochondrial signal. It relieved hyperglycaemia and insulin resistance in a gestational-diabetes model (Yin et al., Pharmacological Research 2022), attenuated lung ischaemia-reperfusion injury through nuclear translocation and antioxidant gene activation (Li et al., Redox Biology 2025), and suppressed ovarian-cancer progression in one 2024 study (Yin et al., Advanced Science 2024).
Mechanism
MOTS-c has no cell-surface receptor in the evidence pack. Two intracellular mechanisms are described. First, nuclear translocation: during metabolic stress the peptide moves into the nucleus and directs expression of nuclear genes to restore cell balance (Kim et al., 2018; Zheng et al., 2023). Second, direct kinase activation: a 2024 study found that MOTS-c modulates skeletal-muscle function by binding and activating casein kinase 2 (Kumagai et al., iScience 2024). An antiviral role has also been reported — in hepatitis B infection, MOTS-c correlated negatively with viral DNA and inhibited replication by 50–70% while promoting mitochondrial biogenesis (Lin et al., Gut 2024).
Human data and the first phase 2 trial
Human evidence is observational and early. Plasma MOTS-c declines with age, and levels have been measured in cohorts such as type 2 diabetics with coronary disease (NCT04027712) and in a hepatitis B cohort where the peptide distinguished chronic infection from healthy controls with an AUC of 0.95 (Lin et al., 2024). The first interventional phase 2 trial — MOTS-c for improving insulin sensitivity in adults with prediabetes and overweight, sponsored by Hudson Biotech (NCT07505745) — was recruiting as of the 2026 snapshot. No efficacy result in humans exists yet.
| Type | Examples | What it supports |
|---|---|---|
| Mouse metabolism | Lee 2015; Yin 2022 | Reduced obesity and insulin resistance |
| Mechanism | Kim 2018; Kumagai 2024 | Nuclear translocation; CK2 activation |
| Human observational | Zheng 2023; Lin 2024 | Age-related decline; biomarker in HBV |
| Human interventional | NCT07505745 (phase 2, recruiting) | Insulin sensitivity — no result yet |
Regulatory status
MOTS-c is not approved anywhere and has no IUPHAR ligand record. It is sold online as a research peptide, usually with claims about exercise, metabolism or longevity that run well ahead of a literature that is almost entirely mouse and cell work plus one recruiting trial. Reviews in the pack describe it as a promising mitochondrial-derived peptide for therapeutic exploitation (Zheng et al., 2023) and one 2025 commentary asks, in its title, whether it is a “magical molecule” for diabetic cardiomyopathy (Yerra & Connelly, Cardiovascular Drugs and Therapy 2025) — the question mark is the point.
MOTS-c vs humanin and other mitochondrial peptides
MOTS-c belongs to a family of mitochondrial-derived peptides encoded by short open reading frames in mitochondrial DNA; humanin, the first discovered, is encoded in the 16S rRNA gene. Both are studied in ageing and metabolism; MOTS-c is the one with a metabolic phenotype in mice and the one now in a phase 2 trial. Because the field overlaps with NAD+ and mitochondrial-function marketing, MOTS-c is frequently sold alongside non-peptide products; the explainer guides linked below separate the chemistry. This profile is educational; it is not guidance on obtaining or using any product and it is not medical advice.
Sequence
One-letter sequence commonly cited for MOTS-c (educational; isoforms and modifications may differ):
MRWQEMGYIFYPRKLR
Residues plotted ~100° apart around an α-helix — clustering of one color reveals an amphipathic face.
Structure & chemistry
Molecular identity & reference confidence
Source-supported reference
Reference values are taken from the cited molecular record or curated profile. A database match is not independent laboratory verification; modifications, counter-ions, and formulations can change the measured mass.
- Molecular form
- Native 16-residue sequence translated from a mitochondrial sORF in the 12S rRNA gene (Lee et al., 2015)
- Species
- Not established by this molecular identity audit
- Termini (N / C)
- Not specified / Not specified
Average reference mass
Reference policy updated: 2026-10-05
- PubChem molecular record · 2026-10-01
- Molecular formula
- C101H152N28O22S2
- Average reference mass
- ≈ 2,174.6
- Receptors
- No classical receptor: acts intracellularly, binding and activating casein kinase 2 (CK2) in skeletal muscle and translocating to the nucleus under stress (Kumagai et al., 2024; Kim et al., 2018)
- Backbone
- Native 16-residue sequence translated from a mitochondrial sORF in the 12S rRNA gene (Lee et al., 2015)
- Status
- Research compound; no approval. Phase 2 trial NCT07505745 (insulin sensitivity in adults with prediabetes and overweight) recruiting in 2026.
- PubChem CID: 146675088
- CAS RN: 1627580-64-6
- UNII: A5CV6JFB78
Chemistry values: curated profile, PubChem · fetched 2026-10-01.
Clinical development snapshot
ClinicalTrials.gov lists 5 registered studies with “MOTS-c” as an intervention (snapshot 2026-09-06). A registry footprint is not evidence of efficacy or approval.
| NCT | Title | Phase | Status | Updated |
|---|---|---|---|---|
| NCT07678073 | Comparison of the Effects of General Anesthesia and Combined Spinal-Epidural Anesthesia on Ferroptosis, Humani | Not applicable | recruiting | 2026-07-08 |
| NCT07505745 | MOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/Obesity | Phase 2 | recruiting | 2026-04-01 |
| NCT03878706 | The Cardiovascular Effect of GLP-1 Agonist, SGLT2 Inhibitor and Their Combination | — | recruiting | 2026-03-13 |
| NCT06133946 | Cohort Of DEafness-gene Screening | — | active not recruiting | 2023-11-18 |
| NCT04027712 | Platelet Reactivity, B-amyloid, MOTS-c and Mortality of Type II Diabetics With CAD | — | unknown | 2019-07-23 |
MOTS-c — reconstitution calculator
Enter how much peptide is in the vial and how much diluent (e.g. bacteriostatic water) is added. The tool returns the resulting solution concentration — and, for any amount you type, the volume it corresponds to. This is educational arithmetic, not a dosing recommendation.
Reference form: Native 16-residue sequence translated from a mitochondrial sORF in the 12S rRNA gene (Lee et al., 2015)Average reference mass: 2,174.6 Da
Enter an amount to see the volume it corresponds to.
Educational concentration mathematics only. This tool does not recommend a dose, amount, or protocol, and nothing here is medical advice. Many peptides are not authorized by Health Canada for human use — see our reconstitution and bacteriostatic-water guides for context.
Change log
Dated observations from the data pipeline (registry flags, trial footprints, identifiers) and editorial reviews of this profile.
- EditorialProfile content reviewed and updated by the editorial team.
FAQ about MOTS-c
What is MOTS-c?+
MOTS-c is a 16-amino-acid peptide (MRWQEMGYIFYPRKLR; C101H152N28O22S2, ≈2,175 Da) encoded by a short open reading frame inside the mitochondrial 12S rRNA gene. Discovered in 2015, it promoted metabolic homeostasis and reduced obesity and insulin resistance in mice, and translocates to the nucleus under metabolic stress to regulate nuclear genes. Plasma levels decline with age. It is a research compound with no approval; its first phase 2 trial, in prediabetes, was recruiting in 2026.
What Canadian product status is recorded for MOTS-c?+
Canadian product status for MOTS-c has not been verified in this profile. No verified record here does not mean no authorization exists. Status depends on the product, formulation and use; consult Health Canada's product records.
What is the typical length of MOTS-c?+
MOTS-c is commonly described as approximately 16 amino acids (Mitochondrial-derived peptide (research compound)).
What is MOTS-c?+
A 16-amino-acid peptide encoded by a short open reading frame in the mitochondrial 12S rRNA gene. In mice it reduced obesity and insulin resistance; it is a research compound, not an approved drug.
What is the sequence of MOTS-c?+
MRWQEMGYIFYPRKLR. Formula C101H152N28O22S2, mass about 2,175 Da.
How does MOTS-c work?+
Intracellularly: it translocates to the nucleus under metabolic stress to regulate gene expression, and binds and activates casein kinase 2 in skeletal muscle. No cell-surface receptor is described.
Has MOTS-c been tested in humans?+
Observationally, yes — plasma levels fall with age. The first interventional phase 2 trial, in adults with prediabetes and overweight, was recruiting in 2026 with no result yet.
Is MOTS-c approved?+
No, nowhere.
MOTS-c vs humanin?+
Both are mitochondrial-derived peptides; humanin comes from the 16S rRNA gene, MOTS-c from the 12S. MOTS-c has the metabolic mouse phenotype and the phase 2 trial.
Further reading
- Not a peptideIs NAD+ a Peptide? No — It Is a Coenzyme. What NAD+, NMN and NR Actually Are and What the Evidence Shows“NAD+ peptide” is a search term with no molecule behind it: NAD+ is a nucleotide coenzyme, not a peptide. This guide explains what NAD+ is, why it appears in peptide catalogues, what the precursors NMN and NR do, what human trials have and have not shown, and the regulatory status of each.
- Not a peptideIs 5-Amino-1MQ a Peptide? No — It Is a Small-Molecule NNMT Inhibitor With Only Animal Data5-Amino-1MQ is marketed next to peptides but is a small quinolinium molecule that inhibits the enzyme NNMT. This guide explains what it is, what the mouse studies showed, why there are no human data, and its regulatory status.
- FoundationsWhat Are Research Peptides? A Clear Educational GuideLearn what “research peptides” means, how they differ from approved peptide drugs, quality markers (COA, purity), and how to study them responsibly.
- SafetyPeptide Safety and Risks: A Balanced Educational OverviewAn objective, balanced overview of what research does and does not establish about peptide risks—unknowns, purity and contamination concerns, and why unapproved compounds carry uncertainty. Not reassurance and not medical advice.
Related peptides
References & further reading
- 1.Lee et al. (2015). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab
- 2.Kim et al. (2018). The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell Metab
- 3.Reynolds et al. (2021). MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun
- 4.Kim et al. (2019). The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity. Physiol Rep
- 5.Hyatt (2022). MOTS-c increases in skeletal muscle following long-term physical activity and improves acute exercise performance after a single dose. Physiol Rep
- 6.Feng et al. (2025). Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion. Free Radic Biol Med
- 7.Lee et al. (2016). MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med
- 8.Lee (2019). Nuclear transcriptional regulation by mitochondrial-encoded MOTS-c. Mol Cell Oncol
- 9.Kim et al. (2021). Mitochondrial-derived peptides in aging and age-related diseases. Geroscience
- 10.Merry et al. (2020). Mitochondrial-derived peptides in energy metabolism. Am J Physiol Endocrinol Metab
- 11.Wan et al. (2023). Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. J Transl Med
- 12.Mohtashami et al. (2022). MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases. Int J Mol Sci
- 13.Kong et al. (2023). Mitochondrial-Encoded Peptide MOTS-c, Diabetes, and Aging-Related Diseases. Diabetes Metab J
- 14.Miller et al. (2022). Mitochondria-derived peptides in aging and healthspan. J Clin Invest
- 15.Yin Y et al. (2022). The mitochondrial-derived peptide MOTS-c relieves hyperglycemia and insulin resistance in gestational diabetes mellitus. Pharmacological Research
- 16.Zheng Y et al. (2023). MOTS-c: a promising mitochondrial-derived peptide for therapeutic exploitation. Frontiers in Endocrinology
- 17.Kumagai H et al. (2024). MOTS-c modulates skeletal muscle function by directly binding and activating CK2. iScience
- 18.Lin C et al. (2024). Novel function of MOTS-c in mitochondrial remodelling contributes to its antiviral role during HBV infection. Gut
- 19.Li X et al. (2025). MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-dependent nuclear translocation. Redox Biology
- 20.PubChem — MOTS-c (CID 146675088)