MOTS-c is a 16-amino-acid peptide encoded within the mitochondrial 12S ribosomal RNA region (the MT-RNR1 locus), first reported by Lee and colleagues in 20151. It is one of a small group of mitochondrial-derived peptides studied as candidate regulators of cellular metabolism. In rodent and cell-culture models, researchers reported that MOTS-c influences glucose handling and activates AMP-activated protein kinase (AMPK) signalling1, and that under metabolic stress it can translocate to the nucleus and associate with the transcription factor NRF22. The published efficacy evidence to date comes from animal and in-vitro work; the available human data are observational, showing that endogenous MOTS-c rises with exercise, and do not involve administering the peptide to people3. MOTS-c is not an approved drug for any indication, and the material described here is intended for laboratory research use only.
Sequence & identity
H-Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg-OH (MRWQEMGYIFYPRKLR) · C101H152N28O22S2 · 2174.6 g/mol
Linear 16-residue peptide. Chemical identity per PubChem CID 146675088 (InChIKey WYTHCOXVWRKRAH-LOKRTKBUSA-N)4.
Mechanisms studied
In published cell and animal studies, MOTS-c was reported to act on the folate-methionine cycle and de novo purine biosynthesis, leading to accumulation of the metabolic intermediate AICAR, which in turn activates AMPK1. Under conditions of metabolic stress such as glucose restriction, investigators observed that MOTS-c moves from the cytoplasm into the nucleus in an AMPK-dependent manner and associates with the stress-responsive transcription factor NRF2, where it was linked to expression of genes carrying antioxidant response elements2. These mechanisms are derived from experimental models and should not be read as established effects in humans.
Dosing in the research literature
The figures below summarise regimens as reported in published research — they are not recommendations or directions for use.
| Source / model | Regimen reported | Notes |
|---|---|---|
| Lee et al., 2015 (Cell Metabolism) — mouse model | As reported in studies: intraperitoneal MOTS-c was administered to mice (e.g. on the order of ~0.5 mg/kg/day in diet-induced obesity experiments). | Animal study. Exact dosing varied by experiment; values are reported for the cited rodent work only and are not human dosing guidance.1 |
| Reynolds et al., 2021 (Nature Communications) — mouse model | As reported in studies: MOTS-c was injected into young, middle-aged and old mice and associated with improved physical performance on running tests. | Animal study. In the human arm of this paper MOTS-c was only measured endogenously after exercise; no peptide was administered to people.3 |
Effects observed in research
In animal and in-vitro studies, researchers reported that MOTS-c administration was associated with improved insulin sensitivity, resistance to diet-induced obesity, and enhanced exercise capacity across age groups13. In humans, the published observation is that endogenous MOTS-c expression in skeletal muscle and plasma increases with exercise3; this is an associative finding and does not demonstrate that administering MOTS-c produces any effect in people. No controlled human efficacy trial of MOTS-c itself has been published.
Strength of evidence
Evidence grade C. The efficacy literature for MOTS-c is built on rodent and cell-culture models123. Human data are limited to observational measurement of naturally occurring MOTS-c levels and do not include administration of the peptide to humans. Pharmacokinetic parameters such as half-life in humans are not established in the peer-reviewed literature. MOTS-c is not approved by Health Canada, the FDA or any regulator for human use, and it is supplied strictly for laboratory research use only.
Reconstitution & storage
Reconstitute with bacteriostatic water for laboratory handling. Store lyophilised material frozen and reconstituted material refrigerated. Use Peptigo’s reconstitution calculator and storage cheat sheet for working figures.
References
- Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443-454. doi:10.1016/j.cmet.2015.02.009.
- Kim KH, Son JM, Benayoun BA, Lee C. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab. 2018;28(3):516-524.e7. doi:10.1016/j.cmet.2018.06.008.
- Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, Lu R, Cohen P, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12:470. doi:10.1038/s41467-020-20790-0.
- National Center for Biotechnology Information. PubChem Compound Summary for CID 146675088, MOTS-c. InChIKey WYTHCOXVWRKRAH-LOKRTKBUSA-N. Accessed June 2026.