MOTS-c is a 16-amino-acid mitochondrial-derived peptide encoded not in the nucleus but within the mitochondrial 12S ribosomal RNA gene. Since its description in 2015 it has become one of the best-characterised members of a small family of peptides that mitochondria appear to use as signalling molecules. This MOTS-c research peptide guide covers its genetic origin, AMPK and folate-cycle mechanism, exercise biology, chemical specification and laboratory handling — research context only.
Key takeaways
- MOTS-c stands for mitochondrial open reading frame of the twelve S rRNA type-c — it is translated from a short ORF inside the mitochondrial MT-RNR1 (12S rRNA) gene.
- Sequence MRWQEMGYIFYPRKLR, 16 residues, CAS 1627580-64-6, formula C101H152N28O22S2, molecular weight ≈2174.6 Da.
- Lee and colleagues (Cell Metabolism, 2015) reported that MOTS-c targets the folate cycle, causing AICAR to accumulate and AMPK to activate, and that it prevented diet-induced obesity and insulin resistance in mice.
- Kim and colleagues (Cell Metabolism, 2018) showed MOTS-c translocates to the nucleus within 30 minutes of metabolic stress in an AMPK-dependent manner and binds antioxidant response element DNA alongside NRF2.
- Reynolds and colleagues (Nature Communications, 2021) found exercise raised MOTS-c roughly 12-fold in human skeletal muscle, and reported large running-capacity gains in treated mice.
- Human evidence remains observational — circulating MOTS-c declines with age and correlates with metabolic disease — not interventional.
- Two methionine residues make the peptide oxidation-sensitive; lyophilised material stored frozen and dark is the stable form.
What is MOTS-c?
MOTS-c is a 16-residue peptide encoded by mitochondrial DNA rather than nuclear DNA, and it is studied as a signalling molecule that mitochondria use to communicate metabolic state to the rest of the cell. It belongs to a small class known as mitochondrial-derived peptides, alongside humanin and the SHLP family.
That origin is what makes it unusual. Almost every peptide in a research catalogue is a nuclear gene product, a fragment of one, or a synthetic analogue. MOTS-c is translated from the mitochondrial genome itself, which places it in a genuinely different category of biology.
Its functional description in the literature is a metabolic stress signal. Under glucose restriction, serum deprivation or oxidative stress, MOTS-c redistributes from mitochondria to the nucleus and participates in adjusting nuclear gene expression — a retrograde signal running from organelle to nucleus.
This guide is for researchers working on mitochondrial signalling, AMPK biology or exercise metabolism, and for purchasing staff who need verifiable chemical specifications. It is not a protocol for administration to any organism.
Where MOTS-c comes from: an ORF inside the 12S rRNA gene
MOTS-c is translated from a short open reading frame located within MT-RNR1, the mitochondrial gene that encodes the 12S ribosomal RNA. The peptide-coding sequence is therefore nested inside a gene whose primary product is a structural RNA — an arrangement that went unnoticed until bioinformatic searches for small mitochondrial ORFs.
Mitochondrial DNA uses a slightly different genetic code from the nuclear genome, and mitochondrial-derived peptides are generally thought to be translated in the mitochondrion and then exported, or in some models translated in the cytosol from mitochondrial transcripts. The details remain an active question.
One practical consequence for researchers is that mitochondrial DNA variants can change the peptide. Sequence polymorphisms within the ORF have been described in population genetics work, which means MOTS-c is not necessarily identical in every individual — a consideration when comparing endogenous measurements across cohorts.
Sequence, structure and chemical specification
MOTS-c is the linear 16-residue peptide Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg, with free N- and C-termini and no post-translational modification in the standard synthetic form. Its composition is mixed: three basic arginine/lysine residues at the C-terminal end, two acidic residues, and a hydrophobic aromatic core.
Two features matter for handling. There are two methionine residues — position 1 and position 6 — which are the most oxidation-prone residues in peptide chemistry. And there is a tryptophan at position 3, which is both oxidation- and light-sensitive. Together these make MOTS-c materially less robust than a simple bioregulator tetrapeptide.
| Property | Value |
|---|---|
| Full name | Mitochondrial ORF of the 12S rRNA type-c |
| Sequence (1-letter) | MRWQEMGYIFYPRKLR |
| Sequence (3-letter) | H-Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg-OH |
| Residues | 16 |
| CAS number | 1627580-64-6 |
| Molecular formula | C101H152N28O22S2 |
| Average molecular weight | ≈2174.6 g/mol |
| Encoding gene | MT-RNR1 (mitochondrial 12S rRNA), internal ORF |
| Net charge at pH 7 | Positive (Arg2, Arg13, Lys14, Arg16) |
| Liability residues | Met1, Met6 (oxidation); Trp3 (oxidation, light) |
| Appearance as supplied | White to off-white lyophilised powder |
| Typical QC methods | RP-HPLC purity, ESI-MS or MALDI-TOF identity |
Mechanism: the folate cycle, AICAR and AMPK
The mechanism reported by Lee and colleagues in 2015 is indirect and elegant: MOTS-c acts on the folate one-carbon cycle, causing the AMPK-activating metabolite AICAR to build up, which in turn switches on AMP-activated protein kinase. The peptide is therefore not a direct AMPK ligand — it changes the metabolite pool that AMPK reads.
AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) is an intermediate of de-novo purine synthesis and a well-known AMPK activator. By interfering with the folate-dependent step that consumes AICAR, MOTS-c raises its concentration. Rising AICAR then activates AMPK, the cell’s principal low-energy sensor.
Downstream, AMPK activation shifts metabolism from anabolic to catabolic: increased glucose uptake and fatty-acid oxidation, reduced lipogenesis. In the 2015 paper, mice given MOTS-c were reported to resist diet-induced obesity and the insulin resistance that normally accompanies it.
Nuclear translocation and stress-responsive gene expression
Kim, Son, Benayoun and Lee reported in 2018 that MOTS-c moves into the nucleus within about 30 minutes of metabolic stress, that this movement requires AMPK, and that once there the peptide binds antioxidant response element DNA sequences. The redistribution is transient — largely reversed within 24 hours.
Three specifics from that paper are worth carrying into experimental design. Blocking AMPK pharmacologically or by knockdown prevented nuclear accumulation. Direct AMPK activators — metformin and AICAR — independently drove MOTS-c into the nucleus. And in the nucleus the peptide interacted with NRF2, enhancing cytoprotective genes including HO-1 and NQO1, with ATF1 binding motifs enriched among regulated genes.
This is a genuinely two-way mechanism: AMPK is both upstream of nuclear entry and downstream of the folate-cycle effect. Treating MOTS-c as a simple linear pathway agonist will misrepresent the published biology.
MOTS-c, exercise and ageing research
The exercise connection is the reason MOTS-c is sometimes called an exercise-mimetic peptide in secondary sources, and it comes from Reynolds and colleagues’ 2021 paper in Nature Communications. That study measured endogenous MOTS-c in exercising humans and then tested the synthetic peptide in mice.
In young human volunteers cycling on a stationary bicycle, skeletal-muscle MOTS-c rose approximately 12-fold after exercise, while circulating levels increased about 1.5 to 1.6-fold and returned to baseline within four hours. That is a measurement of the body’s own peptide, not an intervention.
The mouse arm reported large functional effects. Treated young mice all reached maximum treadmill sprint speed compared with about one in six controls. Old mice at 22 months roughly doubled running duration and covered 2.16 times the distance. Late-life intermittent treatment beginning around 24 months improved grip strength, stride length and walking capacity — described by the authors as compression of morbidity rather than lifespan extension.
What the evidence does and does not show
MOTS-c has a stronger evidence base than most longevity-adjacent research peptides — multiple papers in top-tier journals from independent groups — but the human data is observational, not interventional. No large clinical trial of MOTS-c treatment appears in the literature.
A 2022 review in the International Journal of Molecular Sciences summarises the position: circulating MOTS-c declines with age, with levels in 70–81-year-olds roughly 21% lower than in 18–30-year-olds, and lower levels correlate with type 2 diabetes and cardiovascular dysfunction. Those are associations. Therapeutic evidence remains rodent-based.
| Finding | Model | Source | Strength |
|---|---|---|---|
| Folate-cycle interference raising AICAR, AMPK activation | Cell culture and mice | Cell Metabolism 2015 | Strong mechanistic |
| Resistance to diet-induced obesity and insulin resistance | Mice on high-fat diet | Cell Metabolism 2015 | Rodent |
| AMPK-dependent nuclear translocation; ARE and NRF2 binding | Cell culture | Cell Metabolism 2018 | Strong mechanistic |
| ~12-fold rise in skeletal-muscle MOTS-c after exercise | Human volunteers, endogenous peptide | Nature Communications 2021 | Human observational |
| Improved running capacity and grip strength in old animals | Mice, synthetic peptide | Nature Communications 2021 | Rodent |
| Circulating MOTS-c falls ~21% between young and older adults | Human cohorts | Review, IJMS 2022 | Association only |
| Therapeutic efficacy in people | — | — | Not established |
Laboratory handling, solution preparation and storage
MOTS-c is more oxidation-sensitive than most short research peptides because of its two methionines and single tryptophan, so light exclusion and minimal headspace matter more than usual. The lyophilised powder is the stable form; solutions should be aliquoted and frozen.
- Warm the sealed vial. Let it reach room temperature before breaking the seal to prevent condensation onto the cold cake.
- Select a diluent. Sterile water suits single-use assay solutions; bacteriostatic water with 0.9% benzyl alcohol is used for multi-draw stocks. The peptide is net positive at neutral pH and dissolves readily in aqueous media.
- Add slowly down the wall. Direct the stream onto the glass, then swirl gently. Do not vortex or shake — mechanical stress and air entrainment both promote oxidation.
- Keep it dark. Tryptophan is photosensitive. Work promptly and store solutions in amber vials or wrapped in foil.
- Aliquot at once. Split into single-use volumes and freeze; repeated freeze-thaw cycling causes measurable loss.
- Log the batch. Record compound, batch, concentration, diluent and date on every aliquot for traceability against the certificate of analysis.
| Peptide mass in vial | Diluent added | Resulting concentration | Amount per 0.1 mL | Approx. molar concentration |
|---|---|---|---|---|
| 5 mg | 1 mL | 5 mg/mL | 500 mcg | ≈2.30 mM |
| 5 mg | 2 mL | 2.5 mg/mL | 250 mcg | ≈1.15 mM |
| 10 mg | 1 mL | 10 mg/mL | 1000 mcg | ≈4.60 mM |
| 10 mg | 2 mL | 5 mg/mL | 500 mcg | ≈2.30 mM |
| 10 mg | 5 mL | 2 mg/mL | 200 mcg | ≈0.92 mM |
| 20 mg | 4 mL | 5 mg/mL | 500 mcg | ≈2.30 mM |
Molar values use the free-peptide molecular weight of 2174.6 Da and take no account of counter-ion salt or residual water, so they are upper bounds. Where accurate molarity matters, calculate from net peptide content on the certificate of analysis. Method detail is in the reconstitution guide and stability principles in the storage guide.
MOTS-c in the GenoPept store
Frequently asked questions
What does MOTS-c stand for?
MOTS-c stands for mitochondrial open reading frame of the twelve S rRNA type-c. The name describes its origin: the peptide is translated from a short open reading frame nested inside MT-RNR1, the mitochondrial gene encoding 12S ribosomal RNA. It was first described in a 2015 paper in Cell Metabolism by Lee and colleagues.
What is the amino acid sequence of MOTS-c?
MOTS-c is the 16-residue peptide MRWQEMGYIFYPRKLR — Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg. It carries free N- and C-termini with no post-translational modification in the standard synthetic form. Its molecular formula is C101H152N28O22S2 and its average molecular weight is approximately 2174.6 Da.
How does MOTS-c activate AMPK?
Indirectly. The 2015 Cell Metabolism study reported that MOTS-c interferes with the folate one-carbon cycle, causing the metabolite AICAR to accumulate. AICAR is a well-established AMPK activator, so raising its concentration switches AMPK on. MOTS-c is therefore not a direct AMPK ligand — it changes the metabolite pool that AMPK senses.
Is MOTS-c an exercise mimetic?
That label comes from secondary sources rather than the papers themselves. Reynolds and colleagues reported in 2021 that exercise raised endogenous MOTS-c roughly 12-fold in human skeletal muscle, and separately that synthetic peptide improved running capacity in mice. Those are two different observations, and combining them into a single claim overstates what was shown.
Does MOTS-c need to be kept in the dark?
Yes, it is worth the effort. MOTS-c contains a tryptophan at position 3 that is photosensitive, plus two methionine residues prone to oxidation. Solutions should be prepared promptly, kept in amber vials or wrapped in foil, and stored cold. Avoid vortexing, which entrains air and accelerates oxidation of exactly these residues.
How is MOTS-c different from humanin?
Both are mitochondrial-derived peptides, but they come from different genes and act differently. Humanin is encoded within the 16S rRNA gene and is studied mainly in cytoprotection and apoptosis models. MOTS-c comes from the 12S rRNA gene and is studied in metabolic regulation through AMPK, the folate cycle and stress-responsive nuclear gene expression.
Are there human clinical trials of MOTS-c?
No large interventional trial appears in the published literature. Human data is observational: circulating MOTS-c declines with age — around 21% lower in 70–81-year-olds than in 18–30-year-olds according to a 2022 review — and lower levels correlate with type 2 diabetes and cardiovascular dysfunction. Therapeutic evidence remains rodent-based.
Why does MOTS-c vary between individuals?
Because it is encoded in mitochondrial DNA, which carries population-level sequence variation. Polymorphisms falling inside the MOTS-c open reading frame can alter the peptide sequence in some individuals. That matters when comparing endogenous MOTS-c measurements across cohorts, though it does not affect synthetic material, which is made to the reference sequence.
References
- Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism. 2015;21(3):443–454. DOI
- 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 Metabolism. 2018;28(3):516–524. PubMed
- Reynolds JC, Lai RW, Woodhead JST, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications. 2021;12:470. DOI
- Mohtashami Z, Singh MK, Salimiaghdam N, Ozgul M, Kenney MC. MOTS-c, the most recent mitochondrial derived peptide in human aging and age-related diseases. International Journal of Molecular Sciences. 2022;23(19):11991. DOI
Research-grade MOTS-c, batch-verified
GenoPept supplies MOTS-c as lyophilised vials with a per-batch third-party certificate of analysis covering HPLC purity and mass-spectrometry identity against the 2174.6 Da target mass, dispatched from the UK, strictly for laboratory research.