What it is
MOTS-c is a short chain of 16 amino acids (a peptide). Its recipe is kept in an unusual place. Most of a cell’s DNA sits in its center (the nucleus). But the recipe for MOTS-c is in a small, separate set of DNA inside the mitochondria. Mitochondria are the parts of a cell that turn food into energy. Researchers found the recipe hidden inside a mitochondrial gene. That gene was thought only to help build the cell’s protein-making machinery.
The body makes small amounts of MOTS-c on its own. It can be measured in human blood. The version studied in labs is man-made. Most of what is known comes from mice and from cells grown in a dish. In those studies, it was reported to change how muscle uses 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 first described in 2015. The team was led by Changhan Lee and Pinchas Cohen at the University of Southern California. They worked with researchers at UCLA and the US National Institute on Aging. They found MOTS-c by searching mitochondrial DNA for more hidden peptides. They were looking for peptides like humanin, which Cohen’s lab had studied before.
Lee and Cohen were advisers to CohBar, a California company. They also owned shares in it. CohBar did not develop MOTS-c itself. Instead, it made a changed version called CB4211. It tested CB4211 in a small human study that ended in 2021. In 2026, a company called Hudson Biotech posted a trial listing for MOTS-c itself against a dummy treatment (placebo), at a hospital in Shenzhen, China. But another listing from the same company, for TB-500, says it is a made-up example. So this page does not count the MOTS-c listing as a confirmed trial.
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 shots were reported to stop weight gain on a high-fat diet. They also seemed to prevent blood-sugar problems. Young, middle-aged and old mice could run longer. But these results come from animals. They have not been confirmed in well-controlled human studies.
In people, the evidence so far only comes from measuring. Researchers measured MOTS-c in muscle and blood. Levels were reported to go up after exercise. No results have been published from any trial that gave MOTS-c to people. In 2026, the FDA said it had found no data on people taking it in any way. The first placebo-controlled trial began in 2026. It includes 120 adults with prediabetes (blood sugar that is higher than normal, but not yet diabetes). A related but different molecule, CB4211, was tested for four weeks. Liver fat went down by about the same amount on CB4211 as on the 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) is listed as having started on 2026-02-02; a sibling registration from the same sponsor, site and contact (NCT07487363) describes itself as “a fictional study”, so this record is treated as unverified.
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
There are three separate things to know.
Approval: No medicine containing MOTS-c is approved by the FDA or any other regulator.
Pharmacy mixing (compounding): In September 2023, the FDA put MOTS-c in “Category 2”. This is its list of ingredients that raise safety concerns for pharmacies that mix their own drugs. The FDA said it had found no human data at all. By April 2026, the FDA listed MOTS-c as withdrawn from that list. The pharmacy that had asked for MOTS-c to be reviewed had withdrawn its request. In July 2026, an FDA expert panel voted on MOTS-c. The vote was 7 to 5, and two members did not vote either way (as reported by trade news). The panel advised adding MOTS-c to the list of ingredients pharmacies may use. FDA staff had suggested not adding it. The vote is only advice. The FDA had not made a final decision when this was written.
In October 2026, the US health department (HHS) announced a draft policy. It said it does not intend to take enforcement action against licensed pharmacies or doctors who make single-ingredient MOTS-c products, as long as they follow set conditions, while the FDA writes its final rule. The policy is not binding, and it is not FDA approval. MOTS-c is still not on the official list of allowed ingredients. Comments on the draft are due in mid-November 2026. This page will be updated when a final policy is published.
Sport: Anti-doping lists say MOTS-c is banned.
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 restricted.
On 2026-10-30 HHS published a notice of availability of a draft interim Enforcement Discretion Policy (docket HHS-OASH-2026-0496) covering 503A compounding of MOTS-c and five other peptides. HHS states it does not intend to take enforcement action against state-licensed pharmacies, federal facilities or licensed physicians compounding single-active-ingredient products from bulk substance sourced from an FDA-registered manufacturer with a certificate of analysis, dispensed on patient-specific prescriptions with MedWatch adverse-event reporting, pending rulemaking (the list of peptides and these conditions are taken from the Alliance for Pharmacy Compounding’s summary, because the HHS appendices could not be retrieved for this article). The notice says it is not binding and does not add MOTS-c to 21 CFR 216.23; 503B outsourcing facilities and products sold for “research use” are outside it. FDA staff had recommended against listing. Comments are due about 2026-11-13; no final policy had been published when this was written.
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.
