MOTS-c — Molecular Weight, Sequence & Mitochondrial Research Reference

01What is MOTS-c?

MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a 16-amino-acid peptide with the sequence MRWQEMGYIFYPRKLR, formula C101H152N28O22S2 and a molecular weight of 2,174.6 g/mol. It is encoded within the 12S ribosomal RNA region of mitochondrial DNA and translated from a short open reading frame — an arrangement that was not recognised until its identification in 2015.

Mechanistically the peptide has been linked to AMPK activation and to the folate–AICAR one-carbon pathway, with published work in skeletal muscle glucose handling, diet-induced obesity models and exercise physiology. Circulating MOTS-c has separately been studied as a metabolic biomarker, and endogenous plasma concentrations have been measured in human cohorts.

That last point is where the evidence stops. Measuring endogenous MOTS-c is not the same as characterising administered MOTS-c, and no human pharmacokinetic data for exogenous administration exists. Any half-life figure attached to this compound in secondary sources should be traced to a primary study before it is relied on; this record reports the value as not established.

02Molecular information

03Amino acid sequence

Structural modifications

None. MOTS-c is an unmodified linear L-peptide with a free N-terminal alpha-amino group on Met1 and a free C-terminal carboxyl on Arg16. No acylation, no amidation, no cyclisation, no PEGylation, no non-natural residues. There are no disulfide bonds — the two sulfur atoms in the formula are the thioether sulfurs of Met1 and Met6, not cysteine thiols, though those methionines are oxidation-prone and are the expected degradation/impurity site. A point of genuine biological interest rather than chemical modification: the 51-base-pair open reading frame lies within the mitochondrial 12S rRNA gene, and the encoded peptide corresponds to translation using the standard cytoplasmic genetic code rather than the mitochondrial code, because mitochondrial translation of this ORF would produce tandem start and stop codons [3].

04Pharmacokinetic information

Half-life context

There is no published human pharmacokinetic study of administered MOTS-c. The Alzheimer's Drug Discovery Foundation assessment states plainly that MOTS-c has 'low bioavailability, poor stability, and short half-lives' and that half-life in vivo is 'not yet established' [4]. What has been measured is endogenous behaviour, which is not the same thing: Reynolds et al. showed that in young sedentary men, circulating MOTS-c rose 1.6-fold during and 1.5-fold after acute exercise and returned to baseline within 4 hours of rest, with an 11.9-fold relative increase in skeletal muscle [2]. That 4-hour normalisation describes the endogenous exercise response, not the elimination half-life of an injected dose, and the two must not be conflated. Animal work has used repeated intraperitoneal dosing (5 or 15 mg/kg/day for 2 weeks, or three times weekly in late-life protocols in mice) without reporting PK parameters [2]. Sample stability is itself a documented problem: circulating MOTS-c levels fall by about one quarter when stored at 4°C for 24 hours [4], which complicates comparison of published plasma concentrations across studies. The 2023 Journal of Translational Medicine review contains no pharmacokinetic, half-life, bioavailability or delivery data for MOTS-c [3]. Any single half-life figure quoted commercially for MOTS-c is unsupported.

05Research focus

Primary research areas

• AMPK activation and the folate-AICAR pathway
• skeletal muscle insulin sensitivity and glucose metabolism
• exercise physiology and mitochondrial-nuclear signalling
• diet-induced obesity and metabolic homeostasis in rodents
• age-associated physical decline in mice
• circulating MOTS-c as a metabolic biomarker

Research context

MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a 16-amino-acid peptide, MRWQEMGYIFYPRKLR, identified relatively recently. Lee et al. reported it in Cell Metabolism in 2015 after searching mitochondrial DNA for additional short open reading frames of the kind that had yielded humanin; a 51-base-pair sORF within the mitochondrial 12S rRNA gene encodes the peptide [1]. Its identification in 2015 makes MOTS-c a young research subject relative to the other compounds in this set, and much of the literature is less than a decade old.

The original report described skeletal muscle as the apparent primary target organ and proposed a specific mechanism: MOTS-c inhibits the folate cycle and its tethered de novo purine biosynthesis, causing AICAR accumulation which activates AMPK [1][3]. In mice, MOTS-c treatment prevented age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity [1]. Reynolds et al. subsequently characterised MOTS-c as exercise-responsive: in young sedentary men, skeletal-muscle levels rose 11.9-fold relative to pre-exercise values and circulating levels rose 1.6-fold during and 1.5-fold after exercise, returning to baseline within 4 hours. In mice given intraperitoneal MOTS-c at 5 or 15 mg/kg/day, treadmill running duration and distance increased across young, middle-aged and old animals, and late-life dosing improved grip strength, stride length and walking capacity in very old mice [2].

Human data are observational only. Circulating MOTS-c has been measured in relation to age and metabolic status, though findings are inconsistent across cohorts — reported lower in obese male children and adolescents in one study and higher in obese mothers and newborns in another, with low expression correlating with HbA1c in type 2 diabetes [3]. An independent assessment notes a 6.4% median lifespan increase in aged mice (a trend, p=0.05) and, in humans, no research supporting prevention of cognitive decline [4].

06Research evidence and limitations

Regulatory status

Not approved as a drug in any jurisdiction. MOTS-c is a research-use-only substance with no FDA approval, no EMA marketing authorisation, and no active clinical development programme — CohBar, which developed the MOTS-c analogue CB4211, has dissolved and no ongoing trials were identified [4]. In the United States, FDA added MOTS-c to the list of bulk drug substances for use in compounding that may present significant safety risks (503A Category 2) in October 2023, with the stated concern that 'compounded drugs containing MOTs-C may pose significant risk for immunogenicity' [5]. As of the 22 April 2026 revision of that FDA page, MOTS-c appears among the substances withdrawn from Category 2, part of an announced removal of twelve peptides effective around 22 April 2026, with Pharmacy Compounding Advisory Committee meetings scheduled for 23-24 July 2026 and before February 2027 to consider whether these substances should be added to the 503A bulks list [5]. Removal from Category 2 does not authorise compounding: MOTS-c is not on the 503A bulks list, and the position is best described as unsettled pending FDA and PCAC action. This status is in active flux and must be re-verified at time of publication.

07Research material and sourcing notes

Reported research-use reconstitution information

Supplier technical documentation only (MedChemExpress datasheet HY-P2048A, MOTS-c human acetate): in vitro solubility in water is stated as greater than or equal to 5 mg/mL (2.24 mM), and in DMSO as 4 mg/mL (1.79 mM) with ultrasonic treatment required. No pH value is given. No peer-reviewed reconstitution protocol and no pharmaceutical manufacturer specification exists, because MOTS-c is not an approved product. Preclinical studies administered MOTS-c by intraperitoneal injection in mice without publishing formulation detail [2]. Note that the sample-stability observation above (about 25% loss at 4°C over 24 hours in biological matrix) suggests that prepared solutions should not be assumed stable at refrigerator temperature [4]. No dosing guidance is given here.

Reported storage and stability information

Supplier technical documentation only (MedChemExpress datasheet HY-P2048A). Lyophilised powder: -80°C for up to 2 years, or -20°C for up to 1 year. In solvent: -80°C for up to 6 months, or -20°C for up to 1 month, sealed and protected from moisture. Separately, the ADDF assessment reports that MOTS-c levels in stored samples decrease by roughly one quarter after 24 hours at 4°C [4], which is a stability observation relevant to assay handling rather than a storage specification. No pharmaceutical-grade stability data exists. Methionine oxidation is the expected chemical degradation pathway and argues for storage under inert atmosphere and protection from light where practical.

Identity and sourcing notes

Identity is comparatively tractable for a 16-mer but has specific traps. The two methionines (positions 1 and 6) oxidise readily to methionine sulfoxide, adding 16 Da each; oxidised species are the most common real-world impurity and can be mistaken for a different product on mass alone. Expect and require RP-HPLC purity plus high-resolution MS (free-base monoisotopic 2174.111, average 2174.6) and, ideally, MS/MS sequence confirmation given that the tryptophan and the Arg/Lys content make the peptide susceptible to both oxidation and enzymatic nicking. Salt form must be stated: PubChem records the free base, MedChemExpress supplies an acetate at 2234.64, and TFA salts are widespread; a nominal '10 mg' vial of TFA salt contains materially less peptide than 10 mg free base, so net peptide content on the certificate of analysis matters more than gross mass. Naming is generally consistent — 'MOTS-c', 'MOTS-c (human)' and 'MOTSc' refer to the same sequence — but note that CB4211 is a distinct MOTS-c analogue, not MOTS-c, and clinical data for CB4211 must not be attributed to MOTS-c. Sequence-level check: MRWQEMGYIFYPRKLR. Given documented instability in biological matrix, cold-chain integrity on receipt is a legitimate quality question. This is informational, not promotional.

08References and evidence

Primary sources

1. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistanceprimary literatureLee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P — Cell Metabolism, 2015;21(3):443-454
2. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasisprimary literatureReynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, Lu R, Cohen P, Graham NA, Benayoun BA, Merry TL, Lee C — Nature Communications, 2021;12:470
3. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and agingreviewWan W, Zhang L, Lin Y, Rao X, Wang X, Hua F, Ying J — Journal of Translational Medicine, 2023;21:36
4. MOTS-c — Cognitive Vitality Report for ResearchersreviewAlzheimer's Drug Discovery Foundation — Alzheimer's Drug Discovery Foundation, last updated 17 September 2025
5. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks (MOTS-c listed among withdrawn substances as of the 22 April 2026 revision)regulatoryUS Food and Drug Administration — US FDA, page last updated 22 April 2026

Chemical and molecular databases

• PubChem CID 155885767 (MOTS-c, human) — C101H152N28O22S2, average MW 2174.6 g/mol, exact mass 2174.1110958, CAS 1627580-64-6
• PubChem CID 146675088 (Mots-c) — same molecular formula
• MedChemExpress technical datasheet HY-P2048A, MOTS-c (human) acetate — C103H156N28O24S2, MW 2234.64, solubility and storage (supplier technical documentation)
• Fuku N, et al. 'The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity?', Aging Cell, 2015 — reported association of an mtDNA variant within the MOTS-c ORF with longevity in a Japanese cohort (full text paywalled; bibliographic data only)

09Related compounds

• HumaninThe first-discovered mitochondrial-derived peptide, encoded by a short ORF in the mitochondrial 16S rRNA gene; its discovery is what prompted the mtDNA search that found MOTS-c.Reference page in preparation
• SS-31 (Elamipretide)A mitochondria-targeted tetrapeptide that acts on cardiolipin and mitochondrial bioenergetics — a different chemical class addressing the same mitochondrial-function research question.
• EpitalonThe other compound in this reference set marketed for longevity; both are short peptides with substantial preclinical claims, no established human pharmacokinetics, and the same FDA compounding-list history.
• 5-Amino-1MQA small-molecule NNMT inhibitor studied in the same rodent metabolic and skeletal-muscle literature, frequently compared with MOTS-c as a metabolic/exercise-mimetic research compound.Reference page in preparation
• NAD+Central to mitochondrial energy metabolism and the AMPK/sirtuin signalling network that MOTS-c is proposed to act on, making it the standard metabolic-cofactor comparator in this research area.Reference page in preparation

10Frequently asked questions