MOTS-c
A 16-amino-acid peptide encoded inside the mitochondrial genome that acts as an exercise mimetic by turning on cellular energy switches.
The Mitochondrial-to-Nuclear Energy Switch
Unlike most peptides encoded in nuclear chromosomes, MOTS-c is encoded directly inside mitochondrial DNA. It acts as an “exercise mimetic” communicating cellular energy status back to the nucleus.
1. AMPK Master Switch Activation
Inhibits the folate-methionine cycle, depleting intracellular AICAR and triggering robust activation of 5'-AMP-activated protein kinase (AMPK) — the same enzymatic pathway triggered during endurance exercise.
2. Insulin-Independent Muscle Glucose Uptake
Promotes translocation of GLUT4 glucose transporters to skeletal muscle cell membranes, clearing glucose from the bloodstream even when insulin signaling is impaired.
What is MOTS-c?
MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c) is a 16-amino-acid peptide encoded within the mitochondrial genome rather than nuclear DNA.
Why are people interested in it?
Studied as an 'exercise mimetic' because in animal studies it enhances glucose metabolism, prevents diet-induced obesity, and improves physical performance by activating AMPK.
Primary Research Categories
- Mitochondrial-derived peptides
- Preclinical research compounds
How does it work in the body?
MOTS-c functions as a mitochondrial signaling messenger, activating AMPK and sensitizing muscle tissue to glucose uptake.
Mitochondrial Signaling
AMPK Phosphorylation & Metabolic Homeostasis
AMPK Activation
Acts as an exercise-mimetic signal in skeletal muscle, phosphorylating AMP-activated protein kinase and shifting cells toward fatty acid oxidation.
Glucose Uptake
Stimulates translocation of GLUT4 glucose transporters to muscle cell membranes, enhancing glucose clearance independently of insulin.
AMPK Activation
Turns on the cell's master energy regulator, boosting mitochondrial fatty acid oxidation.
Insulin-Independent Glucose Uptake
Enhances skeletal muscle glucose clearance independently of insulin.
What has actually been demonstrated in humans?
The bulk of MOTS-c research is in rodent models of metabolic syndrome and exercise capacity. Human evidence is limited to observational correlations of circulating plasma levels and an early Phase 1 safety trial.
Pharmaceutical Reality vs. Unregulated Research Chemicals
MOTS-c is an experimental laboratory peptide. It is not approved for any human disease, and is banned in competitive sports by WADA.
What is still uncertain or unknown?
Human therapeutic trial data is lacking. Optimal human dosage, tissue-specific uptake, and long-term metabolic consequences in healthy humans remain uncharacterized.
Companion Resources & Guides
Research at a Glance
Open the full evidence file (3 records)3 records in this file
- ANIMAL1
- REGULATORY2
Publication span: 2015–2026
What Has Actually Been Studied
- FDA — bulk substances nominated for compounding and withdrawn: MOTS-c (FDA compounding communications, 2026) — FDA compounding classification.
- FDA PCAC briefing — MOTS-c-related bulk drug substances (23 July 2026) (FDA PCAC briefing, 2026) — FDA advisory-committee briefing.
- The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance (Cell Metabolism, 2015) — In vivo (mouse) with supporting cellular work.
What is Still Unknown
What we know
- Lee et al. 2015 (Cell Metabolism) is the originating characterisation of MOTS-c in mouse metabolic models.
- No FDA-approved product exists. FDA's withdrawn-nominations table states that human exposure data have not been identified.
- PCAC discussed MOTS-c-related bulk substances on 23 July 2026. FDA briefing materials proposed against inclusion. That is not a listing decision.
Editorial reading of the records below, labelled as Therapept analysis. How records are built
What remains uncertain
- Human interventional data on MOTS-c itself. CB4211 is a related analogue and is not this compound.
- Which PubChem representation a given certificate uses.
Preparation and Handling
Lyophilized peptides ship as freeze-dried powders; whatever happens next involves diluents, concentrations and storage conditions that are compound- and product-specific.
United States Regulatory Status
No FDA-approved product
- No approved drug product exists in Drugs@FDA.
- Listed on FDA's table of bulk substances nominated for compounding and subsequently withdrawn. FDA states it has not identified human exposure data.
- On 23 July 2026 PCAC discussed MOTS-c (free base) and MOTS-c acetate (uses evaluated: obesity and osteoporosis). FDA briefing materials proposed that they NOT be included on the 503A Bulks List. Nominations had been withdrawn; FDA elected to proceed. Committee recommendations are non-binding; FDA has not published a listing decision as of this review.
WADA Anti-Doping Status
Named at S4.4.1 among metabolic modulators, as “mitochondrial open reading frame of the 12S rRNA-c (MOTS-c)”. Prohibited at all times.
Technical Chemical SpecificationsClick to view CAS, sequence, and molecular formulas
- Molecular weight
- 2174.6 g/mol
- Sequence length
- 16 chars
- CAS number
- 1627580-64-6
- PubChem CID
- 146675088
- Compound class
- 16-residue peptide encoded by a short open reading frame in mitochondrial 12S rRNA
- Sequence
- MRWQEMGYIFYPRKLR
- Molecular formula
- C101H152N28O22S2
- Molecular weight
- 2174.6 g/mol
- CAS number
- 1627580-64-6
- PubChem CID
- 146675088
Sources
Last reviewed 12 September 2026 · Compiled by Therapept Editorial · How these records are built