MOTS-c

MOTS-c is a 16-amino-acid peptide encoded not by the cell nucleus but by a short open reading frame within the mitochondrial 12S rRNA gene region of mitochondrial DNA. It was first described by Lee, Cohen and colleagues in 2015 (Cell Metabolism). It belongs to a small, relatively young class of "mitochondrial-derived peptides" (MDPs) that appear to act as signaling molecules, letting mitochondria communicate with the rest of the cell and the body. Circulating MOTS-c has been detected in human blood and rises with exercise, which is why it is often described in the literature as a candidate "exercise mimetic." It is an experimental/investigational compound, not an approved drug.

Education only. This page summarises published research and regulatory status. It is not medical advice and gives no dosing, preparation or administration instructions; any decision about use belongs with an independent qualified professional.

Also known as

MOTS-c (Mitochondrial Open reading frame of the Twelve S rRNA type-c), Mitochondrial-derived peptide c, MOTSc, MOTS-C

Class

Mitochondrial-derived peptide (MDP); metabolic regulator / AMP-activated protein kinase (AMPK) pathway activator

How does MOTS-c work?

Under metabolic stress (such as glucose restriction or exercise), MOTS-c can translocate from the cytoplasm into the cell nucleus, where it helps regulate stress-responsive and antioxidant gene programs (including NRF2-related antioxidant response genes). Its best-characterized metabolic action is on the folate one-carbon / methionine cycle: by interfering with the folate cycle and de novo purine biosynthesis, it causes accumulation of the intermediate AICAR, a known activator of AMP-activated protein kinase (AMPK) — the cell's master energy sensor. Activating AMPK increases glucose uptake into skeletal muscle and shifts cells toward energy production, broadly mimicking some metabolic effects of exercise and caloric restriction. This is summarized as the "folate–AICAR–AMPK" axis.

What has MOTS-c been studied for?

• Insulin sensitivity / insulin resistance (preclinical, plus early human metabolic trials)
• Diet-induced obesity and metabolic homeostasis (animal models)
• Type 2 diabetes / prediabetes and glucose regulation
• Age-related physical decline, muscle function and exercise capacity (mouse models)
• Mitochondrial / metabolic aging and 'exercise-mimetic' signaling
• Bone metabolism, osteoporosis and inflammatory/immune regulation (preclinical, exploratory)
• Non-alcoholic fatty liver disease / NASH (via the engineered analog CB4211)

What does the evidence show?

Evidence is largely preclinical. The strongest data come from cell and rodent studies: in mice, MOTS-c administration prevented diet-induced obesity and insulin resistance, reversed age-dependent muscle insulin resistance, and (in later work) improved physical capacity in aged animals. In humans, endogenous MOTS-c is measurable and increases with exercise, but that is observational biology, not proof that injecting it produces benefits. Direct human efficacy data for exogenous MOTS-c are very limited. The most rigorous human clinical work to date used CB4211, a structurally modified MOTS-c analog (CohBar): a Phase 1a/1b trial in obese subjects with NAFLD reported it was well tolerated and showed early signals (reductions in liver enzymes ALT/AST, a decrease in glucose, a trend toward lower body weight) — but these were small, short (about 4 weeks), exploratory endpoints, not pivotal efficacy proof, and CB4211 is a different molecule from native MOTS-c. A Phase 2a placebo-controlled trial of investigational MOTS-c in adults with prediabetes and overweight/obesity (ClinicalTrials.gov identifier NCT07505745, per secondary reporting) is described as testing insulin sensitivity via the Matsuda Index; readers should verify the trial's existence and status directly at clinicaltrials.gov. Major caveats: most data are animal-only, human trials are early/small, long-term effects are unstudied, much online enthusiasm outruns the evidence, and the grey-market "research peptide" supply has no quality, purity, or dosing assurance.

What is known about the safety of MOTS-c?

A formal human safety profile has NOT been established — USADA notes there are no completed clinical trials defining when, if ever, exogenous MOTS-c is safe to use. Reported or anecdotally associated adverse effects include increased heart rate / palpitations, injection-site irritation, insomnia, and fever; long-term safety is entirely unknown. The engineered analog CB4211 was described as well tolerated with no serious adverse events in a small short-term study, but that does not transfer to unregulated native MOTS-c products. Because grey-market peptides are not pharmaceutical-grade, additional real-world risks include contamination, endotoxin, mislabeled or incorrect dosing, and unsterile preparation. As an AMPK-activating metabolic modulator it could plausibly interact with diabetes medications and affect glucose control. Not studied in pregnancy or breastfeeding. Anyone interested should only consider it in the context of a supervised clinical study or an independent qualified professional's assessment.

What is the legal status of MOTS-c?

Not approved by the FDA (or any major regulator) for any human use; it is an investigational/experimental compound. It is widely sold online only as a "research chemical / not for human consumption," which is a grey-market designation, not an approval. In sport it is BANNED at all times by the World Anti-Doping Agency (WADA) — listed under Section S4.4 Metabolic Modulators, S4.4.1 Activators of AMP-activated protein kinase (AMPK); USADA states no Therapeutic Use Exemption is available because there is no approved therapeutic use. US compounding status, October 2026: on 15 April 2026 the FDA removed MOTS-c from Category 2 of its interim 503A bulk-substances list, where it had been listed over safety concerns, and on 23-24 July 2026 the FDA's Pharmacy Compounding Advisory Committee voted to recommend adding it to the 503A bulks list. The vote is a non-binding recommendation, not a drug approval, and does not by itself let pharmacies compound it. On 14 October 2026 the FDA sent an “Interim Access Policy for Compounding Using Certain Peptides” to the White House Office of Information and Regulatory Affairs for review; as of 21 October 2026 its text and scope were not public and it was not in effect.

What is the half-life of MOTS-c?

Not rigorously established in published human pharmacokinetics. As a small unmodified peptide, native MOTS-c is generally considered to be rapidly cleared from circulation (on the order of minutes to a few hours); reported downstream biological effects (e.g., AMPK activation) may outlast the peptide itself. Notably, the analog CB4211 was deliberately engineered for improved stability and pharmacokinetics precisely because native MOTS-c has limited stability — underscoring that exact half-life figures circulating online are not from robust peer-reviewed human PK data and should be treated as uncertain.

Sources

1. 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.
2. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. Journal of Translational Medicine. 2023. PMC9854231.
3. 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;12:470.
4. MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases. Int J Mol Sci. 2022;23(19):11991.
5. USADA — What is the MOTS-c peptide? (WADA prohibited status & safety)
6. CohBar — Positive Topline Results from Phase 1a/1b Study of CB4211 for NASH and Obesity (press release, Aug 10, 2021).
7. ClinicalTrials.gov NCT07505745 — Phase 2a study of investigational MOTS-c in prediabetes / overweight-obesity (Matsuda Index insulin sensitivity). Per secondary reporting; not directly confirmed at audit time.
8. NCPA: FDA advisory committee nominates six peptides for pharmacies to compound (31 Jul 2026)
9. Frier Levitt: FDA to remove 12 peptides from the Category 2 list (April 2026)
10. Buchanan Ingersoll & Rooney: FDA submits interim peptide compounding policy for White House review (16 Oct 2026)