MOTS-c

What MOTS-c is

MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a synthetic peptide of 16 amino acids, sequence Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg, written in single-letter code as MRWQEMGYIFYPRKLR. It is unusual among catalogue peptides in that its coding sequence does not lie in the nuclear genome. The discovering group, in the laboratory of Pinchas Cohen at the University of Southern California, reported in 2015 that a short open reading frame within the mitochondrial 12S ribosomal RNA gene (MT-RNR1) encodes the peptide, placing MOTS-c among the small set of so-called mitochondrial-derived peptides alongside humanin and the SHLP family [1, 5].

Two features of the molecule bear on how it is handled at the bench. It contains two methionine residues and a single tryptophan, both of which are oxidation-prone, so a certificate should be read with methionine sulphoxide formation in mind. It also carries three arginines and a lysine against two acidic residues, giving the free peptide a net positive charge at neutral pH and good aqueous solubility. There is no cysteine, so no disulphide bridge forms, and there is no lipid modification.

Research-grade MOTS-c is supplied as a white to off-white lyophilised powder, typically as the acetate or trifluoroacetate salt produced by solid-phase synthesis and reversed-phase HPLC purification. The reference identifiers for the peptide are set out in the table below; the values on any batch certificate should agree with them within the precision of the method used. The molecular formula and mass were confirmed against the published sequence and against vendor and reference-database records; the CAS number is in general commercial use for the human sequence.

How the literature describes its mechanism

MOTS-c has no identified cell-surface receptor. The mechanistic literature instead describes two linked ideas: an effect on a cytosolic metabolic pathway, and a stress-dependent movement of the peptide into the cell nucleus.

The original 2015 report proposed that MOTS-c acts chiefly through the folate–methionine cycle and its downstream purine metabolism. In cultured cells and in mice, the authors reported that MOTS-c altered levels of metabolites in the de novo purine biosynthesis pathway, leading to accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an endogenous activator of AMP-activated protein kinase (AMPK). Activation of AMPK was offered as the proximate explanation for the metabolic effects they observed, including improved insulin sensitivity in mice fed a high-fat diet [1]. Because AICAR and AMPK sit at the centre of cellular energy sensing, this placed MOTS-c in the category that anti-doping regulators later described as "AMPK activators" (discussed below).

A second strand of work from the same laboratory, published in Cell Metabolism in 2018, reported that MOTS-c is not confined to the cytosol. Under metabolic stress, principally glucose restriction and oxidative stress, the peptide was reported to translocate to the nucleus, where it was said to associate with stress-responsive transcription factors of the antioxidant-response element and NRF2 pathways and to influence expression of nuclear genes, including those for antioxidant and metabolic programmes [3]. This "retrograde" signalling from a mitochondrially encoded peptide to the nuclear genome is the feature that has attracted the most interest, and it is the mechanism most often cited in reviews. A reader should note that the nuclear-translocation work rests largely on cell-culture imaging and chromatin assays rather than on an independently replicated biochemical account of a direct binding partner.

The broader framework is set out in the 2020 review by Merry and colleagues, which treats MOTS-c together with the other mitochondrial-derived peptides as putative regulators of energy metabolism and situates the AMPK and folate-cycle observations within that literature [4]. The 2022 review by Mohtashami and colleagues surveys the same ground with an emphasis on ageing and age-related disease and is the more recent entry point for a reader new to the field [11]. Both reviews are candid that the mechanistic picture is assembled from a modest number of laboratories and that the molecular detail is incomplete.

For an in-vitro programme, the readouts reported in the primary literature include AMPK phosphorylation, glucose uptake in myotubes and adipocytes, metabolite profiles of the folate and purine pathways, nuclear localisation by immunofluorescence, and expression changes in antioxidant-response genes. As with any peptide lacking a defined receptor, results depend heavily on cell type, glucose and serum conditions, and the stress applied to the culture.

The research record

MOTS-c is a little over a decade old as a named entity, and the great majority of its biology has been established in mice and in cultured cells. There is one clinical programme, built around an analogue rather than the native peptide, and it did not reach a positive efficacy result. These limits should be kept in view.

The discovery paper. Lee and colleagues, in Cell Metabolism in 2015, described the open reading frame, raised antibodies to the peptide, detected it in tissues and circulation, and reported that administration to mice improved metabolic parameters and reduced diet-induced obesity and insulin resistance. This is the foundational paper and the source of the AMPK/folate-cycle mechanism [1]. It is a thorough piece of work, but it is a single discovery study, and the therapeutic observations within it are in mice.

Exercise and ageing in mice. The most cited follow-up is Reynolds and colleagues, in Nature Communications in 2021, which reported that MOTS-c expression and the peptide's nuclear localisation increased with exercise in mouse skeletal muscle and, to a lesser extent, in a small number of human muscle samples, and that treating mice improved running capacity and attenuated age-dependent physical decline [2]. The mouse data are the substance of the paper; the human component is a limited correlational observation and does not establish efficacy in people.

Other mouse models. Several groups outside the originating laboratory have reported effects in specific mouse models. Lu and colleagues, in the Journal of Molecular Medicine in 2019, reported that MOTS-c limited metabolic dysfunction after ovariectomy in mice, acting on adipose tissue [6]. Li and colleagues, in Biochemical and Biophysical Research Communications the same year, reported that MOTS-c improved several markers in a D-galactose-induced ageing model in mice [7]. These are useful because they are not from the Cohen laboratory, but they remain rodent studies in artificial disease models.

Human observational data. There is no controlled human trial of the native peptide. What exists is observational. Cobb and colleagues, in Aging in 2016, measured mitochondrial-derived peptides including MOTS-c in human samples and reported that circulating levels change with age [5]. Ramanjaneya and colleagues, in Frontiers in Endocrinology in 2019, measured MOTS-c in a cross-sectional study and reported that it was significantly lower in people with type 2 diabetes than in controls, and negatively correlated with HbA1c and fasting glucose [8]. Two genetic studies bear on the peptide's relevance in people: Fuku and colleagues, in Aging Cell in 2015, reported that a mitochondrial polymorphism affecting the MOTS-c sequence was associated with exceptional longevity in a Japanese population [9], and Zempo and colleagues, in Aging in 2021, characterised a specific variant (the K14Q substitution) as pro-diabetogenic in a defined genetic background [10]. These are associations in observational cohorts; they describe correlation, not demonstrated benefit of administering the peptide.

The CB4211 clinical programme. The only entity from this family to enter human trials is CB4211, a modified MOTS-c analogue developed by CohBar, Inc., the company co-founded by Pinchas Cohen. CohBar ran a combined Phase 1a/1b study in non-alcoholic fatty liver disease and obesity and reported topline results in August 2021. The Phase 1b stage randomised 20 obese subjects with fatty liver to CB4211 or placebo by daily subcutaneous injection for four weeks. The study met its primary safety endpoint, and the company reported statistically significant reductions in the liver enzymes ALT and AST and in glucose, with a trend toward lower body weight. Critically, however, it did not show a benefit on liver fat over placebo: the reduction in MRI-measured liver fat with CB4211 (about 5.0%) was essentially the same as with placebo (about 4.9%), because the placebo group also improved substantially [13]. CohBar subsequently stated in its 2022 annual filing that it did not consider the formulation used in Phase 1b suitable for further development, that efforts to produce an improved formulation had not succeeded, and that the company had engaged a financial adviser to explore strategic alternatives [13]. The programme did not advance. This is an important data point: the single human programme in this chemical space reached a safety readout but not a positive efficacy result, and it used an engineered analogue, not the native MOTS-c offered here.

Taking the record as a whole. MOTS-c is a genuinely interesting molecule with a plausible and partly independent preclinical literature, a mechanism tied to AMPK and to retrograde mitochondrial-to-nuclear signalling, and suggestive human association data. It also has no controlled trial of the native peptide, a mechanistic account that is still incomplete, and a related clinical programme that did not show efficacy and was not continued. That is a legitimate basis for in-vitro research. It is not a basis for therapeutic claims of any kind, and this page makes none.

Regulatory status in the United Kingdom

MOTS-c is not licensed as a medicine in the UK or anywhere else. It has no marketing authorisation, no pharmacopoeial monograph, and no approved therapeutic use. BuyUK Peptides supplies it as a research chemical for in-vitro laboratory use under the Terms of Sale. It is not for human or veterinary administration. Purchasers must be 18 or over and are responsible for ensuring their use of the material complies with the laws and institutional rules that apply to them. Our guide to the UK rules on research compounds sets this out in more detail.

MOTS-c is prohibited in sport. The World Anti-Doping Agency lists it under section S4 of the Prohibited List, "Hormone and Metabolic Modulators", within the metabolic-modulators subsection, as a named example of an activator of AMP-activated protein kinase (AMPK). The 2025 List cites it explicitly as "mitochondrial open reading frame of the 12S rRNA-c (MOTS-c)" alongside BAM15 and AICAR in the AMPK-activator class. WADA's summary of modifications and UK Anti-Doping's summary of the 2025 changes both record MOTS-c as an added example in the S4 section, noting that it clarifies substances already caught by the class rather than introducing a wholly new prohibition [14]. The S4 prohibition applies at all times, in and out of competition. A validated mass-spectrometry method for detecting MOTS-c in plasma for doping-control purposes has been published, with a reported lower limit of detection around 100 pg/mL, so the compound is testable as well as prohibited [12]. Any researcher whose institution is subject to anti-doping rules should be aware of this.

Handling, storage and stability

MOTS-c is supplied lyophilised in a glass vial with a rubber stopper and an aluminium flip-off crimp. As a 16-residue, unlipidated, cysteine-free peptide it reconstitutes readily, but its two methionines and single tryptophan make it more oxidation-sensitive than a peptide of comparable length without those residues, so protection from air and light matters more here than for some other compounds in the catalogue.

Sealed vial. Store at 2–8 °C for routine use and at −20 °C or below for storage beyond a few months. Protect from light. Avoid repeated freeze–thaw cycles. Allow a refrigerated vial to reach room temperature before opening, so that moisture does not condense onto the cake.

Reconstitution. For most in-vitro work the compound is dissolved in sterile water, bacteriostatic water, or a buffer appropriate to the assay. A positively charged peptide of this length dissolves readily in water; add the solvent down the side of the vial and swirl gently rather than shaking, and the cake should clear within seconds. Sonication is not required and vigorous agitation is best avoided, as it encourages oxidation at the air–liquid interface.

Reconstituted solution. Keep at 2–8 °C and protect from light; use promptly. The conservative practice for a research solution containing oxidation-prone methionine residues is to prepare it fresh, to minimise headspace, and to aliquot into single-use volumes and freeze at −20 °C where the buffer permits, so that the bulk is not subjected to repeated thawing. Discard any solution that develops turbidity or discoloration. The reconstitution calculator gives the volume to add for a target concentration.

Solubility. MOTS-c is freely soluble in water and in common aqueous buffers at the concentrations used in research. Where filtration is required a standard 0.22 µm membrane is adequate. As with any peptide carrying methionine, avoid prolonged exposure to oxidising buffer components and to strong light, both of which accelerate sulphoxide formation.

What a sound certificate for MOTS-c looks like

Every batch we release carries an independent certificate of analysis, and the figures from it are transcribed on the product page and in the certificate register. For MOTS-c a certificate should contain the following, and a reader should be able to check each item against this monograph.

Purity by RP-HPLC. Reversed-phase HPLC on a C18 column with UV detection at 214 or 220 nm reports purity as the area of the main peak as a percentage of all integrated peaks. A good batch of MOTS-c shows a single dominant peak with purity of 98% or above. The characteristic impurity to watch for in this peptide is the methionine-oxidised form, which is 16 Da heavier and often resolves as a small shoulder or an earlier-eluting peak; a certificate that shows the chromatogram is more informative than one that reports a number alone.

Identity by LC-MS. Electrospray mass spectrometry confirms that the main peak has the expected mass. For MOTS-c the average molecular weight is 2174.62 Da. A peptide of this size carrying four basic residues is usually observed as multiply charged ions, commonly the [M+2H]2+ at about 1088.3 and the [M+3H]3+ at about 725.9, and a certificate may report either the observed charge states or a deconvoluted mass. The observed mass should agree with the theoretical value to within about 0.5 Da. A species 16 Da higher than expected indicates methionine oxidation; one 32 Da higher indicates oxidation at both methionines.

Net peptide content. Lyophilised peptides contain bound water and counter-ions, usually trifluoroacetate from purification or acetate after an exchange step, so the mass of powder in the vial exceeds the mass of peptide. Net peptide content, where reported, expresses the fraction that is actual peptide, and it matters for preparing solutions of accurate concentration. A certificate should state which counter-ion is present.

Endotoxin. Where the batch has been tested, a limulus amoebocyte lysate (LAL) result is reported in endotoxin units per milligram. This is relevant to the cell-based assays in which MOTS-c is most often studied, where endotoxin can itself activate stress and inflammatory pathways and confound a metabolic readout.

Our guide to reading a certificate of analysis goes through a complete report line by line.

Related compounds

MOTS-c sits in the catalogue's mitochondrial and coenzyme class, among compounds studied for their effects on mitochondrial function and cellular energy metabolism. It is most naturally discussed alongside SS-31, a mitochondria-targeting tetrapeptide with a quite different mechanism, which concentrates at the inner mitochondrial membrane and interacts with cardiolipin rather than acting through a cytosolic kinase cascade. NAD+, the central redox cofactor of cellular metabolism, is the other point of comparison in this class, relevant to any programme examining AMPK and energy-sensing pathways, in which NAD+ and its sirtuin-linked signalling run in parallel to the AMPK axis that MOTS-c has been reported to engage.

Frequently asked questions

Is MOTS-c made by the body? Yes. The peptide is encoded by a short open reading frame within the mitochondrial 12S rRNA gene (MT-RNR1) and has been detected in human tissues and circulation [1, 5]. The research material supplied here is entirely synthetic.

What is its proposed mechanism? The literature describes activation of AMPK via the folate–methionine and purine pathways, together with stress-dependent movement of the peptide into the nucleus to influence gene expression [1, 3, 4]. No cell-surface receptor has been identified, and the mechanistic account is still incomplete.

Are there any human trials? Not of the native peptide. The only clinical programme used an engineered analogue, CB4211; its Phase 1b study met a safety endpoint but did not show a benefit on liver fat over placebo, and the programme was not continued [13]. Human data on MOTS-c itself are observational and genetic [5, 8, 9, 10].

Is it on the WADA list? Yes. It is prohibited under section S4 (Hormone and Metabolic Modulators) as an example of an AMPK activator, at all times, and a validated detection method exists [12, 14].

What should I do with this material? It is supplied for in-vitro research use only. This page gives no guidance on administration, dosing or human use of any kind, because the compound is not for those purposes.

How long does a sealed vial last? Short lyophilised peptides of this kind are stable for years at −20 °C and for many months at 2–8 °C when kept dry and protected from light. The batch certificate reports the test date; the storage guidance on this page applies from receipt, with the caution that MOTS-c is more oxidation-sensitive than a methionine-free peptide.

References

1. 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:10.1016/j.cmet.2015.02.009. PMID 25738459.
2. 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(1):470. doi:10.1038/s41467-020-20790-0. PMID 33473109.
3. 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.e7. doi:10.1016/j.cmet.2018.06.008. PMID 29983246.
4. Merry TL, Chan A, Woodhead JST, et al. Mitochondrial-derived peptides in energy metabolism. American Journal of Physiology-Endocrinology and Metabolism. 2020;319(4):E659–E666. doi:10.1152/ajpendo.00249.2020. PMID 32776825.
5. Cobb LJ, Lee C, Xiao J, et al. Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Aging. 2016;8(4):796–809. doi:10.18632/aging.100943. PMID 27070352.
6. Lu H, Wei M, Zhai Y, et al. MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction. Journal of Molecular Medicine. 2019;97(4):473–485. doi:10.1007/s00109-018-01738-w. PMID 30725117.
7. Li Q, Lu H, Hu G, et al. Earlier changes in mice after D-galactose treatment were improved by mitochondria derived small peptide MOTS-c. Biochemical and Biophysical Research Communications. 2019;513(2):439–445. doi:10.1016/j.bbrc.2019.03.194. PMID 30967264.
8. Ramanjaneya M, Bettahi I, Jerobin J, et al. Mitochondrial-derived peptides are down regulated in diabetes subjects. Frontiers in Endocrinology. 2019;10:331. doi:10.3389/fendo.2019.00331. PMID 31214116.
9. Fuku N, Pareja-Galeano H, Zempo H, et al. The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity? Aging Cell. 2015;14(6):921–923. doi:10.1111/acel.12389. PMID 26289118.
10. Zempo H, Kim SJ, Fuku N, et al. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging. 2021;13(2):1692–1717. doi:10.18632/aging.202529. PMID 33483425.
11. Mohtashami Z, Singh MK, Salimiaghdam N, et al. 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:10.3390/ijms231911991. PMID 36233292.
12. Knoop A, Thomas A, Thevis M. Development of a mass spectrometry based detection method for the mitochondrion-derived peptide MOTS-c in plasma samples for doping control purposes. Rapid Communications in Mass Spectrometry. 2019;33(4):371–380. doi:10.1002/rcm.8337. PMID 30444551.
13. CohBar, Inc. Announces positive topline results from the Phase 1a/1b study of CB4211 under development for NASH and obesity. Press release, 10 August 2021; and CohBar, Inc. Annual Report (Form 10-K) for fiscal year 2022, filed with the US Securities and Exchange Commission. sec.gov.
14. World Anti-Doping Agency. Summary of Major Modifications and Explanatory Notes to the 2025 Prohibited List; and UK Anti-Doping. 2025 Prohibited List: Summary of Changes. Both published 2024. ukad.org.uk.

This monograph summarises the published literature for laboratory researchers. It is not medical advice, and nothing on this site is for human or veterinary use.