What is MOTS-c?
MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a 16-amino-acid peptide encoded inside the mitochondrial genome rather than the nuclear genome. It was identified in a short open reading frame within the mitochondrial 12S ribosomal RNA gene, and the founding report described it as a regulator of insulin sensitivity and metabolic homeostasis acting mainly on skeletal muscle (Lee et al., 2015).
Because the peptide occurs naturally in tissue and plasma, part of the literature measures endogenous concentrations in people, while the interventional work is cell culture and rodent studies using synthetic peptide. Disguised Alpha supplies MOTS-c as a lyophilized powder for laboratory research use only. Nothing on this page is guidance for use in people.
MOTS-c has no approved drug product anywhere, and reviews of the field note that no established clinical application exists (Zheng et al., 2023). It is tracked by anti-doping laboratories, which have published a validated plasma detection method for synthetic material (Knoop et al., 2019). Our material is research-grade powder, not a drug product, and not for people.
MOTS-c reference data
| Property | Value |
|---|---|
| Name | MOTS-c |
| Aliases | Mitochondrial open reading frame of the 12S rRNA type-c, mitochondria-derived peptide MOTS-c (PubChem CID 146675088) |
| Sequence | Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg (MRWQEMGYIFYPRKLR, 16 residues, PubChem CID 146675088) |
| Peptide class | Mitochondrial-derived 16-residue peptide |
| Molecular formula | C₁₀₁H₁₅₂N₂₈O₂₂S₂ |
| Molecular weight | 2174.6 g/mol |
| CAS number | 1627580-64-6 (PubChem CID 146675088) |
| Salt-form records | PubChem also lists salt entries under the same CAS: a triacetate at 2354.8 g/mol (CID 164946842) and a trifluoroacetate at 2516.7 g/mol (CID 172641109) |
| Form | Lyophilized powder |
| Sizes carried | 10MG, 40MG |
| Testing | Third-party tested, certificate published on the product page and in the COA portal |
Formula, molecular weight, CAS number, peptide class and sizes are from the MOTS-c product page; sequence, aliases and salt-form records are from PubChem. The main figures describe the free peptide, so confirm the salt form, identity and measured content against your lot's certificate before quantitative work.
What the research covers
Published work on MOTS-c falls into six areas. Each summary below states the model used.
Discovery and the folate-AMPK axis
The founding study reported that the peptide inhibits the folate cycle and the de novo purine biosynthesis tethered to it, leading to accumulation of the intermediate AICAR and activation of AMP-activated protein kinase (AMPK), with skeletal muscle as the apparent primary target tissue. In mice, treatment prevented age-dependent and high-fat-diet-induced insulin resistance as well as diet-induced obesity (Lee et al., 2015). Reviews summarize this folate to AICAR to AMPK route as the core reported mechanism (Zheng et al., 2023; Wan et al., 2023).
Signaling between mitochondria and the nucleus
In cell models, MOTS-c moved to the nucleus after metabolic stress in an AMPK-dependent way and regulated nuclear genes, including genes carrying antioxidant response elements, interacting with stress-responsive transcription factors such as NFE2L2 (NRF2). The authors framed this as mitonuclear communication, since a mitochondrially encoded factor regulates the nuclear genome (Kim et al., 2018), and a review developed that into a hypothesis about co-evolved genomes (Benayoun and Lee, 2019).
Skeletal muscle and physical capacity in mice
A study in young (2 month), middle-aged (12 month) and old (22 month) mice reported enhanced physical performance at all three ages, regulation of nuclear genes tied to metabolism and proteostasis, and myoblast adaptation to metabolic stress, with late-life intermittent treatment from 23.5 months also raising physical capacity. In people, exercise raised endogenous expression in skeletal muscle and in circulation (Reynolds et al., 2021).
In a casting model in male C57BL/6J mice, 15 milligrams per kilogram per day over 8 days held muscle mass loss to about 5 percent against 15 percent in immobilized controls, normalized phospho-AKT and phospho-FOXO levels, and lowered circulating inflammatory cytokines and muscle fatty acids (Kumagai et al., 2024). In human and murine muscle progenitor cells, wild-type peptide increased myotube formation while a Y8F mutant did not, which the authors traced to interference with IL-6-driven STAT3 activity (García-Benlloch et al., 2022).
Molecular targets beyond AMPK
Cell-free and mouse work identified casein kinase 2 (CK2) as a direct binding target. The peptide bound CK2 in both fat and muscle but activated it in muscle while suppressing it in fat, suppressing CK2 blunted the muscle effects, and a naturally occurring K14Q variant bound CK2 poorly and did not reproduce them (Kumagai et al., 2024).
A 2026 study in two transgenic mouse strains reported that effects on muscle mitochondrial bioenergetics depended on both PGC-1 alpha and AMPK, happened without a change in respiratory protein content, and came with lower mitochondrial reactive oxygen species emission. In a human knee-extensor protocol in the same paper the arterio-venous difference did not change, which the authors read as evidence that muscle may not be the source of circulating peptide during exercise (Gudiksen et al., 2026).
Genetic variant studies in human cohorts
An Asian-specific mitochondrial DNA variation, m.1382A>C, produces a K14Q replacement in the peptide. A meta-analysis of three cohorts totaling 27,527 people found higher prevalence of type 2 diabetes in male carriers but not female carriers, and in one cohort only among carriers in the lowest tertile of physical activity. In high-fat-fed male mice, wild-type peptide lowered weight and improved glucose tolerance while K14Q peptide did not, and female mice were unaffected (Zempo et al., 2021). An earlier commentary proposed the same variant as a candidate factor in Japanese longevity (Fuku et al., 2015).
Measurement, detection and stability
A liquid chromatography and mass spectrometry method validated for anti-doping use reached a detection limit of 100 picograms per milliliter in plasma and covered four in vitro metabolites and two oxidation products. Endogenous concentrations that a commercial ELISA reported in 20 healthy subjects, 45.9 to 218.5 nanograms per milliliter, could not be confirmed by mass spectrometry (Knoop et al., 2019). That gap matters when reading observational work: a meta-analysis of 7 studies covering 602 participants reported lower circulating concentrations in diabetes and higher in obesity, all by ELISA (Zhou et al., 2024).
Key studies
- Lee C, et al. "The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance." Cell Metab. 2015. PMID 25738459. DOI 10.1016/j.cmet.2015.02.009. Discovery paper: cell culture plus mouse metabolic models.
- 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. PMID 29983246. DOI 10.1016/j.cmet.2018.06.008. Cell culture: nuclear translocation under glucose restriction.
- Knoop A, et al. "Development of a mass spectrometry based detection method for the mitochondrion-derived peptide MOTS-c in plasma samples for doping control purposes." Rapid Commun Mass Spectrom. 2019. PMID 30394592. DOI 10.1002/rcm.8337. Analytical chemistry: validated plasma method and ELISA comparison.
- Benayoun BA, Lee C. "MOTS-c: A Mitochondrial-Encoded Regulator of the Nucleus." Bioessays. 2019. PMID 31378979. DOI 10.1002/bies.201900046. Review of mitonuclear signaling.
- Reynolds JC, et al. "MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis." Nat Commun. 2021. PMID 33473109. DOI 10.1038/s41467-020-20790-0. Young, middle-aged and old mice plus human muscle and plasma after exercise.
- Zempo H, et al. "A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c." Aging (Albany NY). 2021. PMID 33468709. DOI 10.18632/aging.202529. Human cohort meta-analysis (27,527) plus high-fat-fed mouse experiments.
- García-Benlloch S, et al. "MOTS-c promotes muscle differentiation in vitro." Peptides. 2022. PMID 35842023. DOI 10.1016/j.peptides.2022.170840. Human LHCN-M2 and murine C2C12 progenitor cell culture.
- Kumagai H, et al. "Mitochondrial-derived microprotein MOTS-c attenuates immobilization-induced skeletal muscle atrophy by suppressing lipid infiltration." Am J Physiol Endocrinol Metab. 2024. PMID 38170165. DOI 10.1152/ajpendo.00285.2023. Immobilization model in male C57BL/6J mice, with RNA sequencing.
- Kumagai H, et al. "MOTS-c modulates skeletal muscle function by directly binding and activating CK2." iScience. 2024. PMID 39559755. DOI 10.1016/j.isci.2024.111212. Cell-free binding assays, mouse tissue and human K14Q variant carriers.
- Gudiksen A, et al. "MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1 alpha/AMPK-dependent manner." Free Radic Biol Med. 2026. PMID 41520850. DOI 10.1016/j.freeradbiomed.2026.01.002. Two transgenic mouse strains plus a human knee-extensor protocol.
Handling and storage of lyophilized MOTS-c
General laboratory practice for this material:
- Store the lyophilized powder at -20°C, protected from light, until use (storage guidance on the product page).
- Let the sealed vial reach room temperature before opening so moisture does not condense on the powder.
- The sequence carries two methionines (positions 1 and 6) and a tryptophan at position 3, all oxidation-prone. One method study found two oxidation products alongside four in vitro metabolites (Knoop et al., 2019), so limit exposure to air, light and oxidizers and prepare working solutions fresh.
- The peptide is strongly basic (three arginines and a lysine), so expect pH-dependent solubility behavior and keep buffer choice consistent across comparisons.
- After reconstitution, keep solutions at 2 to 8°C and protected from light, and split stock into single-use aliquots to avoid freeze/thaw cycles.
- Record the lot number and keep its certificate with your notes. Supplied material is commonly a salt form, so use the certificate's measured content, not the label mass, for molar calculations.
Frequently asked questions
What is MOTS-c?
MOTS-c is a 16-residue peptide encoded within the mitochondrial 12S ribosomal RNA gene and described as a signaling peptide that acts through the folate cycle, AICAR accumulation and AMPK, with skeletal muscle as its apparent main target tissue (Lee et al., 2015).
Is MOTS-c a peptide the body already makes?
Yes. It is one of the mitochondrial-derived peptides, encoded in mitochondrial DNA rather than the nuclear genome, and it is detectable in tissue and plasma (Lee et al., 2015; Benayoun and Lee, 2019). That is why much of the human literature measures endogenous concentrations rather than testing a synthetic peptide.
MOTS-c vs 5-Amino-1MQ: what is the difference?
They are unrelated chemically and mechanistically: MOTS-c is a 16-residue peptide of about 2174.6 g/mol, while 5-Amino-1MQ is a small-molecule quinolinium inhibitor of nicotinamide N-methyltransferase roughly fourteen times lighter. Our MOTS-c vs 5-Amino-1MQ comparison sets the two side by side.
Why do reported MOTS-c concentrations differ so much between studies?
Method is a large part of it. A validated mass spectrometry method could not confirm the plasma concentrations a commercial ELISA reported in the same reference population (Knoop et al., 2019), and most observational work relies on immunoassay (Zhou et al., 2024). Record the assay when comparing numbers across papers.
How should MOTS-c powder be stored?
Keep the lyophilized powder at -20°C and protected from light. After reconstitution, store the solution at 2 to 8°C, protected from light, and avoid freeze/thaw cycles, as listed on the product page.
Where can researchers buy MOTS-c?
Disguised Alpha sells it for laboratory research, third-party tested with the certificate published on the product page: MOTS-c (10MG and 40MG).
Related compounds and guides
- MOTS-c vs 5-Amino-1MQ: research comparison
- 5-Amino-1MQ and its research guide
- MitoPrime (NAD+ / MOTs-C / 5-Amino-1MQ) and its research guide
- SS-31 and its research guide
- Humanin (Mitochondrial Bioregulator): another mitochondrial-derived peptide
- AICAR and its research guide: the intermediate implicated in the reported AMPK route
- COA portal: every published certificate, by lot
This product is for research use only. It has not been evaluated for safety or effectiveness in humans. Not for human consumption. All products are intended for laboratory research purposes only.