MOTS-c
Also referenced as: mitochondrial open reading frame of the 12S rRNA type-c
A mitochondrial-derived peptide studied in exercise physiology and metabolic regulation.
- Evidence grade
- DPreclinical Research
Preclinical Research
- Regulatory status
- Research Use Only
- Human data
- Limited
No registered clinical trials identified
- Last reviewed
- September 1, 2026
Overview
MOTS-c is encoded within mitochondrial DNA rather than the nuclear genome — one of a small family of mitochondrial-derived peptides discovered in the last two decades.
Levels rise with exercise in humans, which is why it appears in performance discussion. That association is not the same as evidence that administering it improves performance.
Why It's Being Studied
- Insulin sensitivity and glucose metabolism in animal models.
- Exercise adaptation and skeletal muscle metabolic signalling.
- Age-related metabolic decline and mitochondrial-nuclear communication.
Mechanism of Action
It is a signal made inside mitochondria that appears to tell muscle cells to use fuel more efficiently, and it rises naturally with exercise.
MOTS-c targets the folate-methionine cycle, raising AICAR levels and activating AMPK. It also translocates to the nucleus under metabolic stress and binds antioxidant response elements, regulating nuclear gene expression — a documented example of retrograde mitochondrial signalling.
Research Areas & Routes Studied
- Insulin sensitivity
- Exercise metabolism
- Mitochondrial signalling
- Ageing
- Intraperitoneal (animal research)
- Subcutaneous (animal research)
Evidence Summary
A genuinely interesting mitochondrial-derived peptide with strong rodent and cell data, and early human observational work, but no completed randomised human trials.
Human clinical evidence
- Human data are largely observational: circulating MOTS-c rises with acute exercise and differs with age and metabolic status. No administration trials establish clinical effects.
Animal studies
- Mouse studies report improved insulin sensitivity, exercise capacity and reduced diet-induced obesity.
In-vitro studies
- AMPK activation and nuclear translocation characterised in cell models.
Reported Adverse Events in Research
- No human safety data from administration studies.
Limitations of Current Evidence
- Correlational human evidence only.
- Peptide stability and bioavailability in humans are poorly characterised.
Why It Is Used
- Longevity
Energy and Mitochondrial Function
Fatigue that sleep does not fix is the entry point. Mitochondrial compounds are the most biologically interesting and least resolved category on this site.
Read the case study
Research References
- Animal study2015
The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis
Lee C, et al. · Cell Metabolism - Observational study
Exercise induces MOTS-c expression in humans