MOTS-c is a short peptide (16 amino acids) which — unlike almost every other peptide in this encyclopaedia — is encoded not in the cell nucleus but in the DNA of the mitochondria themselves, inside the 12S rRNA gene. Discovered in 2015, it improved insulin sensitivity in mice, protected against obesity and restored physical capacity to old animals, and exercise raised its level in the muscles of volunteers. It sounds like “an exercise hormone in a syringe” — and that is how it is sometimes marketed. The problem is that no study has yet been published in which native MOTS-c was given to humans: what is known about its action comes from mice and cells, and the only completed clinical trial concerned a modified analogue and never appeared in a peer-reviewed journal. In this review we sort out what is fact, what is hypothesis and what is still unknown.
What MOTS-c is
The name stands for “mitochondrial open reading frame of the 12S rRNA-c”. The team of Changhan Lee and Pinchas Cohen (Lee et al., 2015) searched mitochondrial DNA for short “hidden” genes similar to the previously described humanin, and found a fragment encoding a peptide 16 amino acids long. It was named MOTS-c and assigned to the family of so-called mitochondria-derived peptides (MDPs), which also includes humanin and the SHLP peptides. It is therefore a natural signalling molecule that the body produces itself; the “research peptide” of that name is a synthetic copy of it.
How it works — the folate cycle and AMPK
The 2015 paper showed that the main target organ of MOTS-c appears to be skeletal muscle. In muscle cells the peptide inhibits the so-called folate cycle and the purine synthesis coupled to it (purines being building blocks of DNA and ATP). This “blockage” in folate metabolism changes the energy state of the cell and switches on AMPK — an enzyme that acts as a sensor of energy shortage and is also activated during exercise. Hence the description “exercise mimetic”. Kim et al. (2018) added a second element: under metabolic stress (for example glucose deprivation) MOTS-c moves from the mitochondrion to the cell nucleus and there, in an AMPK-dependent manner, regulates gene expression — including antioxidant-response genes, cooperating with the transcription factor NRF2. It was the first description of a molecule encoded in the mitochondrial genome controlling the nuclear genome.
Structure and origin
MOTS-c consists of 16 amino acids. Curiously, the same stretch of DNA serves two purposes: it is part of the 12S rRNA gene (a component of the mitochondrial ribosome) and at the same time encodes the peptide. Because mitochondrial DNA differs slightly between populations, natural variants of MOTS-c exist. The best described is m.1382A>C, found in some inhabitants of North-East Asia — it replaces a lysine with a glutamine in the peptide (the K14Q variant). Fuku et al. (2015) suggested that it might be one of the factors explaining the longevity of the Japanese; that was, however, a short communication with a hypothesis, not proof.
What was studied — cells and animals
The animal data are rich but come largely from a single research community (the University of Southern California and collaborators). In mice MOTS-c prevented age-dependent and high-fat-diet-induced insulin resistance as well as diet-induced obesity (Lee et al., 2015). Reynolds et al. (2021) tested it for physical capacity: the peptide given daily for two weeks to old, 22-month-old mice made them run on a treadmill twice as long and 2.16 times as far as untreated mice; 17% of the old mice reached the fastest stage of the test, versus none in the control group. When treatment was started only late in life (at about 23.5 months) and just three times a week, grip strength, stride length and a walking-test score were better towards the end of life — that is, “healthspan” improved. An extension of lifespan itself was not clearly shown: the survival curves differed only at the borderline of significance.
Human data — levels, exercise and genetics
In humans MOTS-c has been studied only as the body's own molecule — by measuring its level, not by administering it. There are three kinds of such data. (1) Exercise. Reynolds et al. (2021) took muscle biopsies and blood from 10 young, untrained men before and after exercise on a stationary bicycle: the level of MOTS-c in muscle rose 11.9-fold and remained elevated after 4 hours of rest, while in blood it rose 1.6-fold during and 1.5-fold after exercise and then returned to baseline. This is the source of the popular claim that “exercise raises MOTS-c twelve-fold”. But von Walden et al. (2021), in a study of 30 people (endurance exercise, resistance exercise or control), saw only a trend towards higher blood MOTS-c after cycling — humanin, another mitochondrial peptide, rose clearly — and peptide levels were unrelated to fitness or strength. The results are therefore inconsistent and depend on what was measured and when. (2) Metabolism. Cataldo et al. (2018) compared 10 lean and 10 obese people: the blood concentration of MOTS-c was similar (0.48 versus 0.52 ng/ml), but in lean people it correlated with indices of insulin resistance. (3) Genetics. Zempo et al. (2021), in a meta-analysis of three cohorts (27,527 people), showed that men — but not women — carrying the m.1382A>C variant more often have type 2 diabetes, and the risk mainly concerns the least physically active; in mice the K14Q variant did not improve glucose tolerance the way ordinary MOTS-c did. The “longevity” variant of 2015 thus turned out, in another study, to be a diabetes-promoting variant in sedentary men — both observations may be true, but they show how preliminary these data are.
Clinical trials — the CB4211 analogue and the first trial of MOTS-c itself
As of September 2026 there is no publication in PubMed in which native MOTS-c was administered to humans. The only completed clinical trial in this family concerned CB4211 — a modified MOTS-c analogue from the company CohBar, cited in reviews as the sole clinical trial (Kong et al., 2023): a phase 1a/1b study in healthy volunteers and people with fatty liver disease, 88 participants, completed in 2021 (NCT03998514). The registry contains no results and no paper has appeared in a peer-reviewed journal; what is known comes from a company announcement, so we do not quote figures from it. The ClinicalTrials.gov registry does, however, list the first randomised trial of MOTS-c itself: a phase 2a study in 120 adults with prediabetes and overweight, with a daily subcutaneous injection for 12 weeks and insulin sensitivity as the primary endpoint (NCT07505745). Recruitment began in February 2026, and completion of the main part is planned for 2027. Until publication, the statement “MOTS-c works in humans” has no data behind it.
Safety and the limits of the evidence
Since there are no published studies of MOTS-c administration to humans, there are no human safety data either. Mouse studies did not describe toxicity, but rodents are not a tool for assessing safety in people. The mechanism itself raises a few questions worth knowing as questions, not facts: MOTS-c acts by inhibiting the folate cycle, so interactions with drugs acting on that pathway and with the body's folate status cannot be excluded, though nobody has studied them; it switches on AMPK, much as exercise does, so how such stimuli add up remains an open question. On top of that there is a conflict of interest: the authors of most of the key papers are consultants to or shareholders of CohBar, the company that developed the analogue. We deliberately give no methods of use and no doses.
The wider context — mitochondrial peptides
MOTS-c belongs to the mitochondria-derived peptides — alongside humanin and the SHLP peptides — and is the first of them to have reached clinical trials (Kong et al., 2023). Other approaches to “mitochondria in ageing” are SS-31 (elamipretide), a synthetic peptide that stabilises the mitochondrial membrane and has completed phase 3 trials, and the precursors of NAD+ (NMN, NR), tested in more than a dozen randomised human trials. Against that background MOTS-c has the most interesting biology and the least clinical data.
Summary
MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA which, in muscle, inhibits the folate cycle and switches on AMPK, and under metabolic stress moves to the nucleus and regulates genes. In mice it improves insulin sensitivity, protects against obesity and restores running capacity to old animals; in humans exercise raises its level in muscle (almost twelve-fold in one study, only a trend in blood in another), and a genetic variant is linked to diabetes in inactive men. No study of MOTS-c administration to humans has been published; the only completed clinical trial concerned an analogue and has no peer-reviewed results, and the first phase 2a trial of the peptide itself is only now recruiting. State of the evidence: strong biology in mice, observations in humans, zero interventional data.
Sources
- 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. PMID: 25738459. DOI: 10.1016/j.cmet.2015.02.009. pubmed.ncbi.nlm.nih.gov/25738459
- 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. PMID: 33473109. DOI: 10.1038/s41467-020-20790-0. pubmed.ncbi.nlm.nih.gov/33473109
- 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. PMID: 29983246. DOI: 10.1016/j.cmet.2018.06.008. pubmed.ncbi.nlm.nih.gov/29983246
- 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. PMID: 33468709. DOI: 10.18632/aging.202529. pubmed.ncbi.nlm.nih.gov/33468709
- 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. PMID: 26289118. DOI: 10.1111/acel.12389. pubmed.ncbi.nlm.nih.gov/26289118
- Cataldo LR, Fernández-Verdejo R, Santos JL, Galgani JE. Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. Journal of Investigative Medicine. 2018;66(6):1019–1022. PMID: 29593067. DOI: 10.1136/jim-2017-000681. pubmed.ncbi.nlm.nih.gov/29593067
- 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. 2021;131(3):1035–1042. PMID: 34351816. DOI: 10.1152/japplphysiol.00706.2019. pubmed.ncbi.nlm.nih.gov/34351816
- Kong BS, Lee C, Cho YM. Mitochondrial-Encoded Peptide MOTS-c, Diabetes, and Aging-Related Diseases. Diabetes & Metabolism Journal. 2023;47(3):315–324. PMID: 36824008. DOI: 10.4093/dmj.2022.0333. pubmed.ncbi.nlm.nih.gov/36824008
For in-vitro laboratory research only. It is not a human medicine and is not for treatment.