MOTS-c Research, Specifications & Scientific Information

Introduction

Almost every compound in this library is something a chemist designed. MOTS-c is not. It is a sixteen-residue peptide the human body already makes, encoded by a short open reading frame that sits inside the mitochondrial 12S ribosomal RNA gene — a gene that was assumed to code for a structural RNA and nothing else ^[1]. The name is an acronym of that fact: mitochondrial open reading frame of the 12S rRNA-c.

What made the finding interesting was not the peptide but the address. Mitochondria carry their own small genome, and until humanin was identified nobody expected it to encode signalling molecules at all. MOTS-c was the second such peptide found, and the claim built on it is that mitochondria communicate with the rest of the cell — and with the nucleus directly — using factors written in their own DNA ^{[1, 3]}.

The evidence base needs stating plainly, because the compound's reputation runs well ahead of it. The mechanistic and whole-animal work is substantial and published in strong journals. The human work is observational: studies that measure how much of the endogenous peptide is circulating, not studies in which the peptide was administered. One interventional trial is registered and recruiting, with no results ^[8].

This page is a reference record. It describes research. It does not describe use in people or animals, and it carries no guidance of any kind on handling the material.

What Is MOTS-c?

MOTS-c is a sixteen-residue peptide encoded within the mitochondrial genome. It was reported in 2015, found by searching mitochondrial DNA for short open reading frames of the kind that had already yielded humanin ^[1].

Three properties follow from that origin and distinguish it from every incretin analogue described elsewhere in this library.

It is an endogenous sequence, not an analogue. Synthetic MOTS-c is the native human peptide. There is no substitution to resist an enzyme and no fatty acid to bind albumin, because nobody designed it for duration.

It has no established receptor. The characterised actions are intracellular: a change in metabolic flux, and a nuclear one ^{[1, 3]}. No cell-surface receptor is named in the indexed literature, and none is named here.

Its genetics are population-specific in a way protein pharmacology usually is not. Because the coding sequence lies in mitochondrial DNA, it carries mitochondrial variation. A polymorphism in the MOTS-c-encoding region, m.1382A>C, is specific to Northeast Asian populations, and has been proposed — as a hypothesis — as one candidate mechanism behind Japanese longevity ^[2].

MOTS-c is not approved by the U.S. Food and Drug Administration for any indication.

MOTS-c Specifications

MOTS-c is unusual among the compounds in this library in that it is not a designed analogue of anything. It is an endogenous sequence: a sixteen-residue peptide encoded by a short open reading frame lying within the mitochondrial 12S ribosomal RNA gene, which is where its name comes from — mitochondrial open reading frame of the 12S rRNA-c. The synthetic material is therefore the native sequence rather than a stabilised or acylated derivative, and it carries no half-life-extending modification of the kind that defines the incretin analogues. Because it is translated from mitochondrial DNA, its first residue is a methionine and the sequence follows the vertebrate mitochondrial genetic code rather than the nuclear one. The molecular formula and mass shown here are those carried by PubChem compound identifier 146675088 and agree with the supplier catalog record; the two sulfur atoms in the formula are the methionine residues, not a disulfide. The supplier catalog record carries no CAS number for this material, so the CAS number published here comes from the public registers. Any figure on this page is a reference value: the certificate of analysis supplied with a laboratory order is the record for a given lot.

Values that a public register does not carry are shown as not publicly characterised rather than estimated. Identifiers are reference values; the certificate of analysis supplied with a laboratory order is the record for a given lot.

How Does MOTS-c Work?

The mechanism reported for MOTS-c is a metabolic one, and it runs through an enzyme most peptide pharmacology never touches.

The discovery paper reports that the peptide inhibits the folate cycle and the de novo purine biosynthesis tethered to it, and that the consequence of that inhibition is activation of AMP-activated protein kinase ^[1]. AMPK is the cell's principal low-fuel sensor: it switches on when the adenylate ratio falls, and it redirects metabolism away from biosynthesis and towards oxidation. Inhibiting purine synthesis perturbs that ratio, so the route from folate cycle to AMPK is chemically coherent rather than merely correlative.

The second reported action is stranger and, if it holds, more consequential. Under metabolic stress the peptide is reported to move into the nucleus and act on nuclear gene expression directly, in a manner dependent on AMPK ^[3]. The nuclear genome routinely regulates the mitochondrial one; a factor running in the opposite direction is the unusual part of the claim.

Neither mechanism involves a receptor, which is why the conventional pharmacological vocabulary used elsewhere in this library — agonist, affinity, receptor family — does not apply to this compound and is left blank in its specification table.

MOTS-c Mechanism of Action

In vitro research

The cellular characterisation reported alongside the discovery locates the peptide's action in one-carbon metabolism. MOTS-c inhibited the folate cycle and the de novo purine biosynthesis attached to it, and that inhibition led to AMP-activated protein kinase activation; the paper identifies skeletal muscle as the apparent primary target organ ^[1].

The nuclear work extends that. Under glucose restriction, MOTS-c translocated to the nucleus and regulated a broad range of nuclear genes in an AMPK-dependent manner, including genes carrying antioxidant response elements, and interacted with stress-responsive transcription factors regulating those elements, among them nuclear factor erythroid 2-related factor 2 ^[3]. The authors' framing is that the mitochondrial and nuclear genomes co-evolved to encode factors that cross-regulate each other.

A third strand comes from the ageing study, which reported that MOTS-c regulates nuclear genes related to metabolism and proteostasis, and myoblast adaptation to metabolic stress ^[6].

Analytical characterisation of supplied material is a separate exercise entirely. For an unmodified sixteen-residue peptide containing two methionine residues, the practical concerns are oxidation and identity confirmation by liquid chromatography with mass spectrometric detection against a reference standard.

What Is MOTS-c Being Researched For?

The published record has three strands, and they carry very different weight.

• Metabolic and ageing research in mice — insulin sensitivity, diet-induced obesity, physical capacity across the lifespan, and adipose thermogenesis ^{[1, 6, 4]}.
• Mechanistic cell biology — folate-cycle inhibition, AMPK activation, and nuclear translocation ^{[1, 3]}.
• Observational human studies of the endogenous peptide — circulating concentrations in metabolic disease and after exercise, and one genetic-association hypothesis ^{[5, 7, 2]}.

There is one registered interventional trial: a phase 2a study of administered MOTS-c in adults with prediabetes and overweight or obesity, listed as recruiting, with no results posted ^[8]. Until it reports, no human evidence exists about what administering this peptide does.

Human Research on MOTS-c

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

The human literature on MOTS-c is observational. Every study below measured the concentration or expression of the peptide the body makes; none administered it. That distinction is the single most important thing to carry away from this section.

Cross-sectional serum concentrations in metabolic disease

Population. 225 participants in a cross-sectional study: 68 normal, 33 with prediabetes, 31 with type 2 diabetes and HbA1c below 7%, and 93 with type 2 diabetes and HbA1c above 7% ^[5].

Endpoint. Serum concentrations of mitochondrial-derived peptides and of adiponectin, related to biochemical and anthropometric measures by multilinear regression ^[5].

Result. Serum MOTS-c was significantly lower in participants with type 2 diabetes than in controls, p < 0.007. Circulating MOTS-c correlated positively with body-mass index (p < 0.035), total cholesterol (p < 0.0001) and LDL (p < 0.001), and negatively with age (p < 0.002), HbA1c (p < 0.001) and glucose (p < 0.002). In the same participants, humanin showed a stronger and more consistent set of associations, and only humanin correlated independently with HbA1c ^[5].

Limitations. Cross-sectional and associative. A lower concentration in disease says nothing about direction: the peptide may be a consequence of the metabolic state rather than a determinant of it, and this design cannot distinguish the two.

Randomised acute exercise study

Population. 30 participants randomised to endurance exercise (n = 10, 45 minutes of cycling at 70% of estimated maximal oxygen uptake), resistance exercise (n = 10), or control (n = 10) ^[7].

Endpoint and duration. Plasma humanin and MOTS-c, skeletal-tissue MOTS-c, and exercise-related gene expression, measured before exercise and at 30 minutes and 3 hours afterwards ^[7].

Result. Circulating humanin was significantly elevated by acute endurance exercise but not by resistance exercise. MOTS-c showed only a trend to increase after endurance exercise. At rest, humanin correlated with MOTS-c and with age; plasma concentrations of neither peptide correlated with maximal oxygen uptake, leg strength, or mitochondrial DNA copy number ^[7].

Limitations. Thirty participants, one exercise bout, three hours of follow-up. The result on MOTS-c specifically is a non-significant trend, and it is reported here as such because the "exercise-induced" description attached to this peptide is often quoted without it.

Genetic association

The remaining human evidence is a hypothesis rather than a measurement. A 2015 short report notes that the m.1382A>C polymorphism, located in the MOTS-c-encoding region of mitochondrial DNA and specific to the Northeast Asian population, may be among the putative biological mechanisms behind the high longevity of Japanese people — and the authors state in the same breath that more research is needed ^[2]. It is presented here at exactly that strength.

A separate finding from the ageing study belongs in this section because its human component is real: exercise induced endogenous MOTS-c expression in human skeletal tissue and in the circulation ^[6]. That is a measurement of the endogenous peptide, not a trial of an administered one.

Preclinical Research on MOTS-c

Animal research

The animal work is where this compound's reputation comes from, and it is genuinely substantial.

Insulin sensitivity and diet-induced obesity in mice

In the discovery study, administration of MOTS-c to mice prevented age-dependent insulin resistance, prevented high-fat-diet-induced insulin resistance, and prevented diet-induced obesity. The authors' conclusion is framed at the level of biology rather than therapy: that mitochondria may actively regulate metabolic homeostasis at the cellular and organismal level through peptides encoded within their own genome ^[1].

Physical capacity across the mouse lifespan

The 2021 study reports that MOTS-c significantly enhanced physical performance in young mice at 2 months, middle-aged mice at 12 months and old mice at 22 months. It further reports that intermittent administration begun in late life — at 23.5 months, three times a week — increased physical capacity and healthspan ^[6].

The late-life initiation is the part worth noticing. An intervention that works only when started in youth is of limited interest in ageing biology; one begun at 23.5 months in a mouse is begun near the end.

Findings described in this section were observed in animals. Mouse models of metabolic disease and of ageing are standard preclinical tools, and nothing in them establishes anything about humans. The gap is wider here than for most compounds in this library, because there is no human interventional result on the other side of it.

Other Areas of MOTS-c Research

Animal research

Beyond metabolism and ageing, the peptide has been examined in adipose tissue biology. A 2019 study reported that MOTS-c increases adipose thermogenic activation in mice, framing the question around cold adaptation: cold exposure is a stressor with well-described harms, and cold acclimation is the adaptive process that offsets them ^[4].

That work sits in a different literature from the insulin-sensitivity studies but points in a compatible direction, since thermogenic activation of adipose tissue and AMPK-linked metabolic flux are connected processes.

A broader pattern is worth noting about this compound's literature as a whole: MOTS-c has been examined in a wide range of disease models by many groups, but those studies are generally single reports in individual models rather than a coordinated programme, and this page does not enumerate them. What it enumerates are the studies that established the peptide's existence, its mechanism, and its behaviour in whole animals.

Findings described in this section were observed in animals and establish nothing about humans.

Current Research Status

Status as of September 22, 2026. This block is rendered from maintained fields, not from prose, so it cannot go stale in one place and stay current in another.

MOTS-c vs Related Compounds

The useful comparisons for MOTS-c are with the other mitochondrial-derived peptides and with compounds that act on mitochondrial function by other routes.

Within the peptide class

Humanin was the first mitochondrial-derived peptide identified and is the one MOTS-c was found by analogy to ^[1]. The two are frequently measured together, and in the human observational studies cited above humanin often shows the stronger and more consistent associations ^{[5, 7]}.

Mitochondria-targeted, but designed

SS-31 is a synthetic mitochondria-targeting peptide rather than a mitochondrially encoded one. Shared organelle, unrelated origin and unrelated chemistry.

Cofactors rather than peptides

NAD+ participates in the same broad area of mitochondrial and metabolic biology as a coenzyme, not as a signalling peptide. The two are studied in overlapping literatures and act by entirely different means.

Evidence weight

MOTS-c has strong preclinical and mechanistic literature and no published interventional human result. That is the material difference between it and the incretin compounds described elsewhere in this library, and no amount of mechanistic elegance substitutes for it.

No comparison of effect between these compounds is made on this page. Where comparative data exist they belong to the papers that report them.

Chemical & Molecular Characteristics

MOTS-c is an unmodified sixteen-residue peptide. The published sequence is MRWQEMGYIFYPRKLR.

Three points qualify it.

It is translated from mitochondrial DNA. The coding sequence lies within the 12S ribosomal RNA gene and is read using the vertebrate mitochondrial genetic code, which differs from the nuclear code. That is why the peptide begins with methionine and why variation in the sequence is mitochondrial variation, inherited maternally and differing between populations ^{[1, 2]}.

The two sulfur atoms are methionines, not a bridge. The molecular formula C101H152N28O22S2 recorded by PubChem for compound identifier 146675088 carries two sulfur atoms, and both belong to the methionine residues at positions 1 and 5. There is no cysteine in the sequence and therefore no disulfide. Methionine is the residue most prone to oxidation in a lyophilised peptide, which makes oxidation state a real analytical question for this material rather than a theoretical one.

There is no stabilising chemistry. Unlike every acylated analogue described elsewhere in this library, MOTS-c carries no modification intended to extend its residence time. That is a consequence of it being an endogenous sequence rather than a designed drug, and it is part of why the animal studies used repeated administration rather than a long interval ^[6].

The supplier catalog record for this material carries no CAS number. The value published here, 1627580-64-6, comes from the public registers and validates against the CAS check-digit algorithm; UNII A5CV6JFB78 resolves for the same compound, and the formula and mass agree between PubChem and the catalog.

Analytical Specifications

Analytical figures are lot-specific. Fields the catalog does not carry for the current lot are omitted rather than filled with a typical value. The certificate of analysis and the safety data sheet for the exact lot supplied are provided with a laboratory order; no purity figure on this page is a substitute for that document.

Frequently Asked Questions

Scientific 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. PMID 25738459 doi:10.1016/j.cmet.2015.02.009
2. Fuku N, Pareja-Galeano H, Zempo H, et al.. The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity? Aging cell; 2015. PMID 26289118 doi:10.1111/acel.12389
3. Kim KH, Son JM, Benayoun BA, et al.. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress Cell metabolism; 2018. PMID 29983246 doi:10.1016/j.cmet.2018.06.008
4. Lu H, Tang S, Xue C, et al.. Mitochondrial-Derived Peptide MOTS-c Increases Adipose Thermogenic Activation to Promote Cold Adaptation International journal of molecular sciences; 2019. PMID 31109005 doi:10.3390/ijms20102456
5. Ramanjaneya M, Bettahi I, Jerobin J, et al.. Mitochondrial-Derived Peptides Are Down Regulated in Diabetes Subjects Frontiers in endocrinology; 2019. PMID 31214116 doi:10.3389/fendo.2019.00331
6. 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. PMID 33473109 doi:10.1038/s41467-020-20790-0
7. von Walden F, Fernandez-Gonzalo R, Norrbom J, et al.. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans Journal of applied physiology (Bethesda, Md. : 1985); 2021. PMID 34351816 doi:10.1152/japplphysiol.00706.2019
8. MOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/Obesity 2026. NCT07505745

Every identifier above is resolved against PubMed, Crossref or ClinicalTrials.gov at build time, and the title returned by the register is compared with the title stored here. A page does not publish if a reference fails to resolve.

Research-Use Information

For in vitro research use only. This material is a laboratory reagent. It is not a drug, food, dietary supplement, or cosmetic and is not for human or veterinary use, including ingestion, injection, or any other administration. No information on this page describes or implies any effect in humans or animals. Sold only to researchers under our Terms of Sale.

Related laboratory reagent: MOTS-c specifications and lot documentation