What it is
MOTS-c is a short chain of 16 amino acids. What makes it unusual is where its recipe is kept: not in the main DNA in the cell’s nucleus, but in the small, separate set of DNA inside mitochondria, the structures that turn food into usable energy. Researchers found the recipe hidden inside a mitochondrial gene that was thought only to help build the cell’s protein-making machinery.
The body makes small amounts of MOTS-c on its own, and it can be measured in human blood. The version studied in laboratories is made synthetically. Most of what is known comes from mice and from cells in a dish, where it was reported to change how muscle handles sugar and fat. No medicine containing MOTS-c is approved anywhere.
MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a 16-residue peptide, MRWQEMGYIFYPRKLR (C101H152N28O22S2, 2174.6 g/mol), encoded by a short open reading frame within MT-RNR1. It belongs to the mitochondrial-derived peptide family that also includes humanin. Endogenous MOTS-c is detectable in human and rodent plasma.
No cell-surface receptor has been identified. In the founding work its principal target tissue was skeletal muscle, where it inhibited the folate cycle and the linked de novo purine synthesis pathway, leading to AMPK activation. Under metabolic stress, MOTS-c was reported to translocate to the nucleus in an AMPK-dependent manner and to interact with stress-responsive transcription factors such as NRF2 (Kim et al., Cell Metab 2018).
In-vivo pharmacokinetics have not been published. FDA’s 2026 review found only an in-vitro study in which MOTS-c was rapidly cleaved in human whole blood into N-terminally truncated fragments (residues 2–16 to 5–16), and noted it is unknown whether injected peptide reaches active concentrations.
Who made it and when
MOTS-c was described in 2015 by Changhan Lee, Pinchas Cohen and colleagues at the University of Southern California, working with researchers at UCLA and the US National Institute on Aging. They found it by searching mitochondrial DNA for more hidden peptides like humanin, which Cohen’s laboratory had studied before.
Lee and Cohen were consultants to and shareholders of CohBar, a California company. CohBar did not develop MOTS-c itself; it designed a modified relative called CB4211 and tested it in a small human study that ended in 2021. In 2026 a company called Hudson Biotech registered the first placebo-controlled trial of MOTS-c itself, at a hospital in Shenzhen, China.
Lee et al. reported MOTS-c in Cell Metabolism in March 2015 after screening mtDNA for short open reading frames, prompted by the earlier identification of humanin. In mice, MOTS-c prevented high-fat-diet-induced obesity and insulin resistance and reversed age-dependent insulin resistance. Follow-up work from Lee’s laboratory described nuclear translocation (Kim et al., 2018) and effects on physical capacity across ages (Reynolds et al., Nat Commun 2021). The 2018 paper discloses that Lee consulted for and held shares in CohBar; the 2021 paper discloses the same for both Lee and Cohen.
CohBar, Inc. (Menlo Park, California) developed CB4211, which it described as “a novel and improved analog of MOTS-c”, and ran a Phase 1a/1b study (NCT03998514) from 2018 to 2021. No later-phase CB4211 trial has been registered. No compound patent covering MOTS-c could be verified for this article, so none is listed. The Phase 2a MOTS-MET trial (NCT07505745) is sponsored by Hudson Biotech at Peking University Shenzhen Hospital; Hudson Biotech also sponsors a 2026 BPC-157 trial at the same hospital.
What the data say
In mice, MOTS-c injections were reported to prevent weight gain and blood-sugar problems on a high-fat diet, and to improve running capacity in young, middle-aged and old animals. Those results come from animals and have not been confirmed in controlled human studies.
In people, the evidence so far is observational: MOTS-c levels in muscle and blood were measured and reported to rise after exercise. No results from any trial giving MOTS-c to humans have been published, and the FDA said in 2026 that it had found no human exposure data by any route. The first placebo-controlled trial, in 120 adults with prediabetes, began in 2026. A related but different molecule, CB4211, was tested for four weeks; liver fat fell by about the same amount on it as on placebo.
Animal data: Lee et al. (2015) reported that MOTS-c injections prevented diet-induced obesity and insulin resistance in mice. Reynolds et al. (2021) reported improved physical performance in mice aged 2, 12 and 22 months, and increased physical capacity when intermittent dosing three times weekly began at 23.5 months. Rodent studies summarised by FDA also report osteogenic effects and suppression of vascular calcification; FDA noted that none assessed dose-response, the molecular target is unknown, and no acute, repeat-dose, genotoxicity, reproductive or carcinogenicity studies exist.
Human data: exercise increased endogenous MOTS-c in human skeletal muscle and plasma (Reynolds et al.). FAERS searches through March 2025 retrieved no adverse-event reports. MOTS-MET (NCT07505745; Phase 2a; n=120 planned; subcutaneous once daily for 12 weeks; primary endpoint Matsuda insulin-sensitivity index) started on 2026-02-02.
Analogue data: in CB4211 Part C (NCT03998514), 20 adults with obesity and NAFLD received 25 mg subcutaneously once daily or placebo for 4 weeks. MRI-PDFF liver fat fell by a similar amount in both arms (5.03 versus 4.88 points); ALT (−21% versus +4% on placebo), AST and glucose reductions were reported as significant in a company release.
Regulatory picture
Three separate facts. Approval: no medicine containing MOTS-c is approved by the FDA or any other regulator. Compounding: in September 2023 the FDA put MOTS-c in “Category 2”, its list of ingredients that raise safety concerns for pharmacy compounding, saying it had found no human data at all. By April 2026 the FDA listed MOTS-c as withdrawn from that category by the pharmacy that had nominated it. In July 2026 an FDA advisory committee voted 7 to 5, with two abstentions (as reported by trade press), to recommend adding it to the list of allowed compounding ingredients, even though FDA staff had proposed not adding it. The vote is advice only; the FDA had not made a final decision when this was written. Sport: anti-doping databases list MOTS-c as prohibited.
Approval: none. No US IND-stage programme for MOTS-c itself could be verified; MOTS-MET lists a single Chinese site, and CB4211 is a distinct molecule.
Compounding: MOTS-c entered 503A Category 2 on 2023-09-29. The only nomination, from Wells Pharmacy Network, was withdrawn, and FDA’s safety-risk page (updated 2026-04-22) lists MOTs-C among substances previously in Category 2 withdrawn by their nominators. FDA nevertheless evaluated MOTS-c (free base) and MOTS-c acetate on its own initiative for the 2026-07-23 Pharmacy Compounding Advisory Committee. Its briefing concluded that the criteria weighed against inclusion: the substances were not well characterised, there were no nonclinical toxicology studies, and there were no human safety or effectiveness data. The committee voted 7–5 with two abstentions in favour. Inclusion in 21 CFR 216.23 would require notice-and-comment rulemaking, so this article records compounding status as unknown pending that decision.
Sport: FDA’s briefing notes that the Global DRO database lists MOTS-c as prohibited, drawing on the 2024 WADA Prohibited List class of hormone and metabolic modulators.
