MOTS-c
MOTS-c is a 16-amino-acid peptide encoded within the mitochondrial 12S rRNA gene, described in 2015 as a regulator of metabolic homeostasis. Research is mainly in cell and rodent models, with limited human data.
Overview
MOTS-c belongs to a class of mitochondrial-derived peptides, short peptides encoded by small open reading frames within mitochondrial DNA. It was described by Pinchas Cohen's group at the University of Southern California in a 2015 Cell Metabolism paper, which reported that it acts on skeletal muscle metabolism and insulin sensitivity in mice. The discovery added to evidence that mitochondria can produce signaling peptides that act beyond the organelle.
Since then, MOTS-c has been studied in models of obesity, insulin resistance, exercise capacity and aging, and circulating levels have been measured in human observational studies. Most mechanistic evidence comes from cell and rodent work. In July 2026 the FDA's Pharmacy Compounding Advisory Committee voted 7-5, with two abstentions, to recommend adding MOTS-c to the 503A bulk drug substances list. The vote is advisory, and no final FDA action has been announced.
Compare: MOTS-c vs SS-31, Humanin vs MOTS-c.
Structure
MOTS-c is a linear 16-residue peptide with the sequence Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg (MRWQEMGYIFYPRKLR). It is encoded within the mitochondrial gene for 12S ribosomal RNA. It contains two methionines and one tryptophan, all oxidation-prone, and has several basic residues that make it strongly cationic. Research material is usually supplied as an acetate or trifluoroacetate salt.
Mechanism
In the original mouse and cell studies, MOTS-c was reported to inhibit the folate cycle and de novo purine synthesis, leading to accumulation of the intermediate AICAR and activation of AMP-activated protein kinase (AMPK), a central regulator of cellular energy balance. Skeletal muscle was identified as a principal target tissue. Later work from the same group reported that, under metabolic stress, MOTS-c can translocate to the nucleus and influence expression of genes involved in antioxidant and stress responses. A cell-surface receptor has not been identified.
Research
Metabolism and insulin sensitivity in mice
The 2015 study reported that MOTS-c prevented diet-induced obesity and insulin resistance in mice and improved glucose handling, with skeletal muscle as a key site of action. Subsequent rodent studies have explored effects on fat metabolism and glucose regulation. These are animal findings, and how well they translate to human metabolism has not been established in controlled trials. Later studies from other groups have been broadly supportive but not uniform.
Exercise capacity and aging models
Later research from the discovering group and others reported that MOTS-c levels change with exercise and age, and that treatment improved measures of physical performance in older mice. Exercise and aging studies in rodents are informative but do not establish comparable effects in people, and some findings await broader replication. Exercise-induced increases in circulating MOTS-c have also been reported in small human studies, which are correlational.
Human observational data
Circulating MOTS-c has been measured in human cohorts, with associations reported between levels and factors such as age, insulin sensitivity and exercise. These are correlational studies; they do not show that MOTS-c causes any of these changes. Immunoassay-based measurements of small peptides can also vary between laboratories, which complicates comparison across studies. Results across cohorts have not always been consistent in direction or magnitude.
Clinical development
Human interventional data on MOTS-c itself are very limited. Analogues based on MOTS-c have entered early clinical development, but published results are sparse. MOTS-c therefore remains largely a preclinical research compound, and the FDA advisory committee's 2026 vote reflected a split view of the available information. Questions about identity, characterization and quality of compounded material were also raised in the committee's discussion of peptides at that meeting.
Regulatory status
MOTS-c is not approved by the FDA for any use. In July 2026 the FDA's Pharmacy Compounding Advisory Committee voted 7-5, with two abstentions, to recommend adding MOTS-c to the Section 503A bulk drug substances list. FDA's own reviewers had recommended against, the vote is advisory, and FDA must act through notice-and-comment rulemaking. No final FDA action has been announced. For sport, check the current WADA Prohibited List.
Status changes often. See the regulatory tracker for dated updates.
Quality and identity testing
A MOTS-c certificate of analysis should confirm identity by mass spectrometry against the expected mass shown on this page and report HPLC purity with a chromatogram. Key pitfalls are oxidation of the two methionines and the tryptophan, which give +16 Da and related species, and deletion or truncation sequences that are common in a 16-residue synthesis. The salt form and net peptide content should be stated; because the peptide has several basic residues, it can carry multiple counter-ions, which lowers peptide content per milligram.
Open MOTS-c in the sequence analyzer to see the expected [M+H]+ and multiply charged ions for an MS identity check.
For a walkthrough of each section of a certificate, see how to read a COA.
Storage and stability
Store lyophilized MOTS-c sealed at -20 °C or below, protected from light and moisture. With two methionines and a tryptophan, the peptide is vulnerable to oxidation, so limit air and light exposure and avoid long storage in solution. Allow vials to warm before opening, aliquot any prepared solution, and avoid repeated freeze-thaw cycles. Cationic peptides can adsorb to some plastics and glass at low concentrations.
Download the MOTS-c data sheet (PDF): sequence, masses, expected MS ions and handling on one printable page.
Latest research
The newest PubMed-indexed papers that mention MOTS-c in their title or abstract, retrieved through Europe PMC and refreshed automatically. Inclusion is not an endorsement of a paper's findings.
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Frequently asked questions
Is MOTS-c FDA approved?
No. MOTS-c is not approved by the FDA for any use. In July 2026 the FDA's Pharmacy Compounding Advisory Committee voted 7-5, with two abstentions, to recommend adding it to the 503A bulk drug substances list. That vote is advisory, FDA's own reviewers had recommended against, and no final FDA action has been announced.
Where does MOTS-c come from?
MOTS-c is encoded by a short open reading frame within the mitochondrial gene for 12S ribosomal RNA. That makes it a mitochondrial-derived peptide, encoded in mitochondrial DNA rather than in the nuclear genome. It was described in 2015 by researchers at the University of Southern California, who reported that it acts on metabolism in mice.
What is a mitochondrial-derived peptide?
A mitochondrial-derived peptide is a short peptide encoded by a small open reading frame within mitochondrial DNA. Humanin was the first described, and MOTS-c is another well-known example. These peptides are thought to act as signals between mitochondria and the rest of the cell or other tissues, although their biology is still being worked out, largely in cell and animal studies.
Related compounds
- SS-31 (elamipretide)
SS-31, known as elamipretide, is a synthetic mitochondria-targeted tetrapeptide that binds the inner-membrane lipid cardiolipin. It received FDA accelerated approval in September 2025 as Forzinity for Barth syndrome.
- NAD+
NAD+ (nicotinamide adenine dinucleotide) is not a peptide; it is a dinucleotide coenzyme essential for redox metabolism and a substrate for sirtuins, PARPs and CD38. It is studied in aging and metabolic research.
- 5-Amino-1MQ
5-Amino-1MQ is not a peptide; it is a small-molecule quaternary quinolinium compound that inhibits the enzyme nicotinamide N-methyltransferase (NNMT). It has been studied in cell and rodent models of obesity and metabolism.
- Epitalon
Epitalon is a synthetic tetrapeptide (Ala-Glu-Asp-Gly) developed by Vladimir Khavinson's group in St. Petersburg, based on a pineal gland extract. It is studied in aging and telomere research, with evidence coming mostly from that group.
References
- Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015. Find on PubMed
- PubMed: all indexed literature on MOTS-c
- ClinicalTrials.gov: registered studies mentioning MOTS-c
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