MOTS-C
A peptide encoded by mitochondrial DNA, studied as a communication signal between the mitochondrion and the rest of the cell in metabolic regulation.
What if the mitochondrion did more than produce energy? MOTS-C, encoded by its own DNA, opened a research avenue on how it communicates with the rest of the cell.
- Research Use Only
- Molecule under study
- Living document
- Current research state
- Basic and preclinical research, with a registered phase 2a human trial of native MOTS-C. No results from this trial are yet available and there is no authorised medical use.
- Current clinical phase
- Phase 2a registered for the native peptide — no published results
- Last update
- 25 septembre 2026 · Fiche v1.1
- Living document
- Updated regularly as research progresses.
What is MOTS-C?
MOTS-C (Mitochondrial Open reading frame of the Twelve S rRNA type-c) is a 16-amino-acid peptide. Its sequence is hidden within the mitochondrial gene that encodes 12S ribosomal RNA.
It belongs to the family of 'mitochondrial-derived peptides' (MDPs), alongside humanin. This family revealed that the mitochondrion can produce small signals able to act beyond itself.
MOTS-C is detected in blood and tissues. Its levels vary with age, metabolic status and physical activity, which has attracted interest from research on metabolism and ageing.
Names you may come across
MOTS-C is referred to under a few similar spellings, all derived from its original publication.
The most common spelling in research catalogues.
Full name behind the MOTS-c acronym, as published in the original article (Cell Metabolism, 2015).
Name of the family it belongs to, together with humanin and SHLPs.
Understanding it simply
Three simple markers to understand MOTS-C.
A message from the mitochondrion
The mitochondrion is often described as the cell's 'powerhouse'. MOTS-C shows it can also send messages.
An energy sensor
MOTS-C appears to act on a cellular system called AMPK, which helps cells manage and use energy. This link is studied mainly in the laboratory and in animals.
Mostly animal evidence
Effects on glucose, insulin or endurance were observed in mice. In humans, mostly blood levels are measured.
What research shows today
Science advances step by step. We clearly distinguish what is firmly established from what remains under study.
- MOTS-C is a 16-amino-acid peptide encoded within the mitochondrial 12S ribosomal RNA gene (MT-RNR1). — établi
- It was first described in 2015 (Lee et al., Cell Metabolism). — établi
- In cellular and mouse models, it is associated with activation of the AMPK pathway. — établi
- Its circulating levels rise during exercise in humans in published studies. — établi
- The effect of exogenous MOTS-C in humans is not established. — en cours
- Pharmacokinetics, safety and dose-response in humans: not characterised. — en cours
Described mechanisms and consistent preclinical data (cells, mice). In humans, a phase 2a trial of the native peptide is registered, but no interventional results have yet been published.
Level of evidence, step by step
- Biochemical mechanism3/4
Folate → AICAR → AMPK pathway described in several publications.
- Cell (in vitro)3/4
Effects reproduced in several cell types.
- Animal (in vivo)3/4
Mouse data on metabolism, exercise and ageing.
- Human1/4
Published observational data and a registered phase 2a trial; no interventional results are available for the native peptide.
What the research shows
- In mice fed a high-fat diet, MOTS-C limited weight gain and insulin resistance (Lee et al., 2015).
- Under metabolic stress, MOTS-C can move to the nucleus and modulate gene expression there (Kim et al., 2018).
- In older mice, its administration improved physical performance parameters; in humans, exercise increases its muscle and circulating levels (Reynolds et al., 2021).
What still remains to be studied
- No results from an interventional clinical trial of native MOTS-C have yet been published; a phase 2a trial is registered and its results are not available.
- Associations between circulating levels and metabolic status in humans do not demonstrate cause and effect.
- MOTS-C assay methods vary from study to study, which complicates comparison of results.
What science shows
Laboratory / cells
- In cells, MOTS-C appears to change how energy is managed and can enter the nucleus when the cell is under stress.
- It appears to act on a system called AMPK, which helps cells manage and use energy.
Animals
- In mice, studies have observed effects on glucose use, insulin sensitivity, adaptation to exercise and some age-related changes.
- These results are promising, but a result in mice does not prove effectiveness in humans.
Humans
- Published human studies have mainly measured naturally occurring MOTS-C in blood or muscle, particularly in relation to exercise, age and metabolic health.
- These observations show associations, but do not prove that administering MOTS-C provides a medical benefit.
Clinical trials
- No results from an interventional clinical trial of native MOTS-C have yet been published.
- A phase 2a human trial is registered to study, among other outcomes, insulin sensitivity in adults with prediabetes and overweight or obesity. Results are not yet available.
- CB4211 reached a phase 1a/1b trial, but it is an analogue engineered from MOTS-C: it is not native MOTS-C, and its results must not be treated as results for the native peptide.
What we know today
Not all information carries the same weight of evidence. We therefore present it across three clearly distinct levels, from the most solid to the most indicative.
What scientific publications show
Scientific evidence- Publications converge on a role for MOTS-C in metabolic signalling in animals.
- The link with exercise is one of the most reproduced human observations.
- Authors stress the need for controlled trials before any clinical conclusion.
What some professionals report
Documented- MOTS-C is cited in reviews on mitochondrial ageing as a research avenue, not as a treatment.
- CB4211, an analogue derived from MOTS-C but distinct from the native peptide, underwent a phase 1a/1b trial.
What the community reports
Field observations- Informal reports circulate about energy or endurance; they are unverified.
- No individual observation replaces controlled clinical data.
The gap between preclinical results and human evidence remains large: caution before any extrapolation.
What does the medical community say?
- Scientific interest in peptides produced by mitochondria is genuine, particularly for understanding metabolism and ageing.
- Human clinical data nevertheless remain insufficient to conclude that native MOTS-C has established medical benefits.
- MOTS-C is not currently an approved medicine for energy, endurance, metabolism or longevity.
- The term ‘exercise mimetic’ does not mean it replaces exercise: some biological pathways activated by MOTS-C merely resemble those engaged by exercise in experimental studies.
Why biohacking is interested
- Biohacking communities are mainly interested in it for energy, endurance, metabolism, fatigue, mitochondrial health and longevity.
- These are exploratory uses, hypotheses and personal experiences. Its popularity has grown faster than the clinical evidence.
What people report online
Positive experiences mentioned
- A feeling of greater energy or a subjective reduction in fatigue.
- Better workout endurance or a feeling of being able to train for longer.
Other experiences reported
- No noticeable effect for some users; fatigue or headaches for others.
- Injection-site reactions, redness, swelling or flu-like symptoms have been reported.
- Palpitations or a racing-heart sensation are mentioned in some accounts.
These uncontrolled reports cannot demonstrate that an effect was caused by the molecule.
What we know today
- MOTS-C is a natural peptide encoded by mitochondrial DNA.
- Its experimental effects on cellular energy, glucose and exercise are documented mainly in cells and animals.
- A phase 2a trial of the native peptide is registered, with no results available to date.
What we do not know yet
- Its clinical effectiveness, safety and long-term effects in humans.
- The true meaning of the associations observed with exercise, age and metabolic health.
- Whether promising animal findings can be reproduced in humans.
How does MOTS-C work?
Preclinical work describes a chain of events linking MOTS-C to the cell's energy metabolism.
Described inhibition of the folate cycle and purine synthesis.
Accumulation of AICAR, a metabolic intermediate that activates AMPK.
Activation of the cellular energy sensor, associated with improved glucose uptake in muscle.
Under stress, nuclear translocation and modulation of stress-response genes.
This cascade is described in vitro and in mice. Its importance in humans has not been demonstrated.
Timeline des essais cliniques
A molecule under study progresses step by step. Here, simply, is where the research currently stands.
- Discovery· 2015Completed
Identification of MOTS-C
Lee et al. describe the peptide and its metabolic effects in mice.
- Research· 2015Completed
Genetic variant and longevity
Fuku et al. study the m.1382A>C variant in a Japanese population.
- Research· 2018Completed
Nuclear translocation
Kim et al. show that MOTS-C reaches the nucleus in response to metabolic stress.
- Research· 2021Completed
Exercise and ageing
Reynolds et al. link MOTS-C to exercise and age-related physical decline.
- Ongoing· ActuellementOngoing
Registered phase 2a trial
A trial of native MOTS-C is studying, among other outcomes, insulin sensitivity in adults with prediabetes and overweight or obesity; no results are yet available.
Les analyses disponibles
The theory is put to the test. Here are the independent analyses already published for MOTS-C, available in the Analyses Library.
Ouvrir la bibliothèque des analysesQuestions fréquentes
Is MOTS-C a medicine?
No. No health authority has authorised MOTS-C. It is presented here solely in a research context.
Why is it said to come from the mitochondrion?
Established: its sequence is encoded by mitochondrial DNA, in the 12S ribosomal RNA gene, not by nuclear DNA.
Do effects observed in mice apply to humans?
To be studied: no published clinical trial demonstrates it. Animal results are a research basis, not clinical proof.
What is the link with physical exercise?
Established: in humans, exercise increases MOTS-C levels measured in muscle and blood. The functional meaning of this rise remains to be clarified.
Is there a clinical trial of MOTS-C?
Yes. A phase 2a trial of the native peptide is registered. It studies, among other outcomes, insulin sensitivity in adults with prediabetes and overweight or obesity, but no results are yet available.
What adverse effects are known in humans?
To be studied: in the absence of published clinical trials on the native peptide, its tolerability profile in humans is not characterised.
Publications scientifiques
Selection of reference publications on MOTS-C — discovery, mechanisms, exercise and ageing. Evolving bibliography.
Mitochondrial peptides modulate mitochondrial function during cellular senescence
Kim S. J. et al. · Aging · 2017
Glossaire
- Mitochondrion
- Cell organelle that produces most of the cell's energy and has its own DNA.
- AMPK
- Enzyme that detects energy shortage in the cell and activates pathways that produce it.
- Energy homeostasis
- Balance between the energy supplied, stored and spent by the body.
- Insulin resistance
- Reduced tissue response to insulin, which hinders glucose use.
- Preclinical
- Research stage preceding human trials: laboratory work and animal models.
- Observational study
- Study that measures and compares without intervening; it shows associations, not causes.
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Fiche de référence — version 1.1, mise à jour le 25 septembre 2026. The complete regulatory and scientific framework is gathered in the « Information importante » en tête de fiche.