MOTS-c Peptide: The Mitochondrial-Derived Peptide

MOTS-c is a 16-amino-acid peptide (MRWQEMGYIFYPRKLR, molecular weight 2174.6 g/mol) encoded not in the nuclear genome but in mitochondrial DNA, inside the gene for the 12S ribosomal RNA. It was described in 2015 by Changhan Lee, Pinchas Cohen and colleagues at the University of Southern California, who linked it to the folate pathway, de novo purine synthesis and activation of AMP-activated protein kinase (AMPK). It is investigational: no drug containing it is approved anywhere, and it is named on the World Anti-Doping Agency's 2026 Prohibited List.

This profile sets out what is established about the molecule: its identity, how a peptide came to be found inside a ribosomal RNA gene, the mechanism described in the literature, the cell and animal systems it has been studied in, its regulatory position, and the handling points that matter when it arrives in a lab as a lyophilized powder.

Identity at a glance

The values below come from the PubChem record for MOTS-c (CID 146675088) and the originating paper.

A few structural points follow from the sequence. Four residues are basic (Arg2, Arg13, Lys14 and Arg16) against one acidic residue (Glu5), so the peptide carries a clear net positive charge at neutral pH. The two sulfur atoms in the formula belong to two methionines (Met1 and Met6), not to cysteines, so there are no disulfide bonds. The combination of two methionines and a tryptophan (Trp3) matters in storage, because these are the residues most prone to oxidation. The C-terminal half is rich in aromatic and hydrophobic side chains (Tyr8, Ile9, Phe10, Tyr11, Leu15). For a primer on how residues, termini and bonds define a peptide in general, see what peptides are.

Where MOTS-c came from

Human mitochondrial DNA is a circular genome of about 16.6 kilobases. Its classical gene content is 13 protein-coding genes, 22 transfer RNAs and two ribosomal RNAs, the 12S and 16S rRNAs. The discovery of humanin, a peptide encoded by a short open reading frame (sORF) within the 16S rRNA gene, raised the question of whether mitochondrial DNA held other small coding sequences hidden inside genes that had been annotated as non-coding.

Lee and colleagues searched the 12S rRNA gene for such sequences and reported, in Cell Metabolism in 2015, a 51 base pair sORF that encodes a 16-residue peptide. Sixteen codons plus a stop codon account for the 51 bases. They named the peptide MOTS-c, for mitochondrial open reading frame of the 12S rRNA-c.

One detail in the original paper explains a puzzle about how the peptide is made. Mitochondria use a genetic code that differs from the standard one in a few codons. The authors reported that reading this sORF with the mitochondrial code gives tandem start and stop codons, while the standard code gives a viable peptide, and they concluded that MOTS-c translation occurs in the cytoplasm. The same paper reported the peptide in several rat and mouse tissues and in human and rodent plasma using a MOTS-c-specific ELISA. Because rats lack the nuclear copies of mitochondrial sequences (NUMTs) found in humans, the authors argued that mitochondrial DNA was the only possible source of the peptide in that species.

MOTS-c is one of a small group now called mitochondrial-derived peptides, alongside humanin and the small humanin-like peptides encoded in the 16S rRNA gene. Material sold for research today is made by solid-phase peptide synthesis, not isolated from tissue.

Endogenous MOTS-c: expression, tissues and plasma

The mitochondrion is usually described as the organelle that makes ATP. MOTS-c is part of the evidence that it also sends signals. Because it is a peptide encoded by mitochondrial DNA that turns up outside the organelle, several papers call it a mitochondrial signaling peptide, and Reynolds and colleagues note that it has been dubbed a "mitochondrial hormone" or "mitokine".

Three observations about endogenous MOTS-c recur in the literature:

• Where it is found. The 2021 Nature Communications paper by Reynolds and colleagues describes MOTS-c expression as age-dependent and detected in multiple tissues, including skeletal muscle, and in circulation. The same paper cites earlier work associating aging with reduced MOTS-c levels in skeletal muscle and in plasma.
• Response to exercise. In that study, ten sedentary young men exercised on a stationary bicycle, and skeletal muscle and plasma were collected before exercise, after it, and again after a four-hour rest. Western blotting showed that endogenous MOTS-c levels in skeletal muscle rose 11.9-fold after exercise, and an ELISA showed that circulating endogenous MOTS-c also rose, 1.6-fold during the session. The paper's title calls the mitochondrial-encoded MOTS-c an exercise-induced regulator of age-dependent physical decline and muscle homeostasis.
• How it is measured. Plasma MOTS-c levels are measured by immunoassay. As with any small peptide, an antibody signal is not proof of the 16-residue sequence, so quantitative claims about levels of MOTS-c in plasma are only as good as the assay behind them.

These are measurements of the body's own peptide. They describe the expression of MOTS-c, not the effect of MOTS-c added from outside, and the two questions should be kept apart when reading the literature.

Function of MOTS-c: the molecular mechanism in the literature

No cell-surface receptor for MOTS-c has been identified. The mechanism described in the literature is intracellular and runs through one-carbon metabolism.

• Folate pathway and purine synthesis. In the 2015 paper, cells engineered to express MOTS-c showed depletion of 5-methyltetrahydrofolate and a block in de novo purine biosynthesis. The purine intermediate 5-aminoimidazole-4-carboxamide ribonucleotide (the monophosphate, often called ZMP) accumulated more than 20-fold compared with control cells, and a smaller increase was seen after adding synthetic MOTS-c to HEK293 cells.
• AMPK activation. That intermediate is the same molecule that the research tool AICAR is converted into inside cells, and it activates AMPK by mimicking AMP. The authors proposed that this accumulation partly accounts for the AMPK activation they measured. The compound AICAR is covered in its own profile.
• Nuclear translocation. A 2018 follow-up by Kim and colleagues reported that under metabolic stress, such as glucose restriction, MOTS-c moves into the nucleus in an AMPK-dependent manner. There it was associated with changes in the expression of a broad set of genes, including genes with antioxidant response elements, and it interacted with stress-responsive transcription factors such as NRF2 (NFE2L2). The authors presented this as evidence that a mitochondrial-encoded factor can regulate nuclear gene expression.

A third line of work concerns stress adaptation. Reynolds and colleagues identified heat shock factor 1 (HSF1) as a putative transcription factor behind the gene-expression changes seen after MOTS-c treatment in mouse skeletal muscle and in myoblasts. Taken together, these papers suggest that MOTS-c targets nuclear gene expression as well as cytoplasmic metabolism, which is why reviews describe the role of MOTS-c as communication from the mitochondrion to the cell nucleus. Humanin and MOTS-c are the two best-studied examples of that idea.

The upstream event remains open. How MOTS-c enters cells when added externally, what it binds first, and how it acts on the folate pathway at the level of a specific enzyme are not settled in the published record.

A naturally occurring variant

Because MOTS-c is encoded in mitochondrial DNA, sequence variants in the population change the peptide directly. Zempo and colleagues (Aging, 2021) described the variant m.1382A>C (rs111033358), reported as specific to Asian populations, which replaces lysine 14 with glutamine (K14Q). The study combined genetic association data from three cohorts with mouse experiments and cell assays; in vitro, the K14Q form showed reduced insulin-sensitizing activity compared with the reference sequence. For laboratories, the practical point is that "MOTS-c" in a paper usually means the reference sequence in the table above, and the K14Q form is a distinct molecule, even though its mass is almost the same.

Research models: where the effect of MOTS-c has been studied

The published work on MOTS-c falls into a few groups, all described here neutrally:

• Cell culture. HEK293 cells and engineered cell lines stably expressing MOTS-c, used for metabolomic profiling, AMPK signaling and nuclear translocation studies.
• Rodent models. Mouse studies of diet-induced insulin resistance and age-related metabolic change, including the original 2015 work in mice on a high-fat diet, and male and female mice fed a high-fat diet in the 2021 variant study.
• Myoblast culture. In the 2021 study, MOTS-c in C2C12 mouse myoblasts was tested under glucose restriction and serum deprivation. Cells treated with MOTS-c or vehicle control were compared for survival by crystal violet staining and for oxygen consumption in the presence of palmitate.
• Aging mouse cohorts. The same study used young (2 months), middle-aged (12 months) and old (22 months) mice treated with MOTS-c, with treadmill running, skeletal muscle metabolomics and gene expression as readouts.
• Human observational data. Measurement of circulating MOTS-c by immunoassay, and genetic association studies of the m.1382A>C variant.
• Registered human trials. ClinicalTrials.gov lists a Phase 2a, randomized, double-blind, placebo-controlled study of MOTS-c in adults with prediabetes (NCT07505745), sponsored by Hudson Biotech and recruiting as of October 2026. Its primary outcome measures are an insulin sensitivity index and the incidence of adverse events. No findings are posted.

Two cautions apply when reading this body of work. Reported effects of MOTS-c treatment come almost entirely from cell and rodent experiments, and a response to MOTS-c in a mouse is not evidence about people. And the phrases that fill secondary sources, that MOTS-c may do one thing or that data suggest that MOTS-c does another, usually trace back to the handful of primary papers cited here.

Most of the mechanistic literature comes from a small number of groups, several sharing authors. Two authors of the original papers have disclosed consulting and shareholding relationships with CohBar, Inc. That is normal in translational biology, and it is also a reason to watch for independent replication.

Regulatory and anti-doping status

MOTS-c is not an approved drug in the United States or elsewhere. Its current position has three parts:

1. FDA compounding review. FDA lists MOTS-c among bulk drug substances that may present significant safety risks in compounding, citing possible immunogenicity and the complexity of peptide-related impurities and characterization. At its July 23, 2026 advisory committee meeting on compounding, the agency proposed that neither MOTS-c free base nor MOTS-c acetate be included on the 503A Bulks List.
2. No approved product. There is no FDA-approved product containing MOTS-c, and no marketing authorization in other major jurisdictions. FDA's compounding page also states that the agency has not identified any human exposure data on drug products containing MOTS-c and lacks important information on safety issues it might raise.
3. Sport. The World Anti-Doping Agency's 2026 Prohibited List names MOTS-c under S4.4.1, activators of AMP-activated protein kinase, within S4, hormone and metabolic modulators. That class is prohibited at all times, in and out of competition. AICAR is named in the same entry. In short, MOTS-c is prohibited for anyone competing under the World Anti-Doping Code.

Material from Anhydrolabs is supplied for in-vitro laboratory research only; see the research-use terms.

Laboratory handling and storage

MOTS-c is supplied as a lyophilized powder in vacuum-sealed vials, sold singly on the MOTS-c catalog page and as 10-vial kits. Its sequence suggests a few specific handling points.

Solubility. With four basic residues and one acidic residue, MOTS-c is a basic peptide, and basic peptides generally dissolve well in water or a dilute acidic buffer. The hydrophobic stretch in the C-terminal half can slow dissolution at higher concentrations, so add solvent gently down the vial wall and swirl rather than vortex. The general procedure for in-vitro stock solutions is covered in how to reconstitute lyophilized peptides.

Oxidation. Two methionines and a tryptophan make oxidation the main chemical risk. Methionine sulfoxide adds 16 Da per oxidized residue, which shows up clearly in mass spectrometry. Keep headspace small, avoid repeated opening, and consider degassed buffers for long experiments.

Storage. Keep the sealed powder frozen, dry and away from light, and let the vial reach room temperature before opening so moisture does not condense on the cake. Once in solution, divide the stock into single-use aliquots and freeze them; repeated freeze-thaw is a common source of degradation. The practical detail is in how to store peptides and the site's storage and handling page.

Identity and purity. Check the certificate of analysis for a mass consistent with 2174.6 g/mol and for purity measured as the area of the principal peak in reversed-phase HPLC. A +16 Da species points to methionine oxidation, and a +1 Da species can indicate deamidation of Gln4. The K14Q variant, by contrast, differs from the reference sequence by only about 0.04 Da, so ordinary mass checks cannot tell the two apart; that takes tandem MS or sequencing. The method is explained in how HPLC measures peptide purity.