Metabolic

MOTS-c Peptide

Reviewed 22 October 2026 · How we research

Also known as: MOTS c, MOTSc, Mitochondrial ORF of the 12S rRNA type-c

What is MOTS-c?

MOTS-c is one of a handful of peptides encoded not in the cell nucleus but in mitochondrial DNA — specifically inside the 12S rRNA gene. Its discovery in 2015 helped establish a new class called mitochondrial-derived peptides, alongside humanin.

It attracts interest because in mice it behaves like an “exercise mimetic”: it improved insulin sensitivity, prevented diet-induced obesity and improved physical capacity in older animals. Natural MOTS-c levels in humans rise with exercise and tend to fall with age.

How MOTS-c works

MOTS-c acts mainly in skeletal muscle. It inhibits the folate cycle, which builds up the metabolite AICAR and activates AMPK — the cell's energy sensor and the same pathway exercise and metformin engage. Under metabolic stress MOTS-c also moves into the nucleus, where it regulates genes involved in antioxidant defence and stress adaptation.

What the research shows

• Mice given MOTS-c were protected from high-fat-diet obesity and insulin resistance (Lee et al., 2015).
• Exercise raised circulating MOTS-c in humans, and treating old mice improved running capacity and muscle function (Reynolds et al., 2021).
• Lower MOTS-c levels have been associated with insulin resistance and type 2 diabetes in observational human studies.
• An analogue (CB4211) entered early human trials for fatty liver disease and obesity; no MOTS-c product is approved.

MOTS-c side effects

There are no published controlled human trials of MOTS-c itself, so its side-effect profile in people is unknown. Anecdotal reports describe injection-site reactions and transient fatigue or increased heart rate. Absence of evidence is not evidence of safety.

UK legal status

MOTS-c is not a licensed medicine in the UK and is supplied only as a research peptide. Because it activates AMPK, competitive athletes should treat it as falling under WADA's metabolic-modulator prohibitions.

More detail, including current UK research-vial prices: MOTS-c UK guide. For the doses used in published studies and the reconstitution maths: MOTS-c dosing in the literature.

References

1. Lee C, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21:443–454.
2. Reynolds JC, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12:470.
3. Kim KH, et al. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab. 2018;28:516–524.