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MOTS-c is a 16-amino-acid peptide encoded not in the cell nucleus but in mitochondrial DNA. Since its discovery in 2015 it has been studied mainly for its effects on metabolism, through activation of the energy sensor AMPK. This overview covers what MOTS-c is, how it is thought to work, the key studies and how to handle research vials.
What is MOTS-c?
MOTS-c belongs to a small group called mitochondrial-derived peptides (MDPs). Its gene sits inside the mitochondrial 12S rRNA region (MT-RNR1), a stretch of DNA long thought to code only for ribosomal RNA.
Key facts
- Sequence: MRWQEMGYIFYPRKLR (16 amino acids)
- Approx. molecular weight: 2,174.6 Da
- Origin: mitochondrial 12S rRNA gene
- Related peptides: humanin and the SHLP family (encoded in 16S rRNA)
How MOTS-c is thought to work
The proposed mechanism has three steps, set out in the original paper:
- Folate cycle inhibition: MOTS-c slows the methionine–folate cycle.
- AICAR build-up: this blocks de novo purine synthesis, so the intermediate AICAR accumulates.
- AMPK activation: AICAR is a known AMPK activator, switching cells towards glucose uptake and fatty acid use.
A 2018 follow-up showed MOTS-c can also move into the nucleus under metabolic stress and influence gene expression, which makes it an example of mitochondria signalling back to the nucleus.
Key MOTS-c studies
2015: discovery (Cell Metabolism)
Lee et al. reported that MOTS-c targeted skeletal muscle and, in mice, prevented diet-induced obesity and insulin resistance. Read the original paper.
2018: nuclear translocation (Cell Metabolism)
Kim et al. showed that under glucose restriction or oxidative stress, MOTS-c enters the nucleus and regulates antioxidant-response genes.
2021: exercise and ageing (Nature Communications)
Reynolds et al. found MOTS-c levels rise with exercise in humans, and that treatment improved physical performance in young, middle-aged and old mice.
Important context: almost all of this work is in cells and rodents. Human data is limited to observational measurements of circulating levels.
MOTS-c vs other metabolic research peptides
- MOTS-c: acts inside cells via the folate cycle and AMPK.
- GLP-1 agonists such as semaglutide: act on cell-surface receptors involved in appetite and insulin release.
- Multi-agonists such as retatrutide: combine GLP-1, GIP and glucagon receptor activity.
Different mechanisms mean they answer different research questions, which is why MOTS-c appears in mitochondrial and ageing studies more than appetite studies.
Handling MOTS-c research vials
- Before reconstitution: store the lyophilised powder at −20°C, away from light.
- After reconstitution: refrigerate at around 4°C and avoid freeze–thaw cycles.
- Calculations: use the peptide calculator to work out concentration for a 10mg vial.
See our guide to lyophilised vials for more on why peptides are freeze-dried.
MOTS-c FAQs
What does MOTS-c stand for?
Mitochondrial Open reading frame of the Twelve S rRNA type-c. The name describes where in the mitochondrial genome the peptide is encoded.
Who discovered MOTS-c?
It was described in 2015 by Changhan Lee, Pinchas Cohen and colleagues at the University of Southern California, published in Cell Metabolism.
Is MOTS-c the same as humanin?
No. Both are mitochondrial-derived peptides, but humanin is encoded in the 16S rRNA gene and MOTS-c in the 12S rRNA gene. They have different sequences and research focuses.
Is MOTS-c legal in the UK?
MOTS-c can be sold in the UK for research use. It is not a licensed medicine and falls under WADA restrictions for athletes.
Summary
MOTS-c is a mitochondrial-encoded peptide studied for metabolic regulation through the folate cycle and AMPK, with promising animal data and limited human evidence. PeptidesNextDay supplies MOTS-c 10mg at ≥98% purity, dispatched same day on orders placed by 3pm (Mon–Fri), with batch documentation available on request.