MOTS-c — mitochondrial open reading frame of the 12S rRNA type-c
16-residue mitochondrial-derived peptide. AMPK activator and metabolic regulator.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
FDA-tracked compound — synthesized for clinical/research use
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FDA-tracked (reclassified Category 1, Feb 2026) — preclinical/clinical bioassay data exists
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Snapshot
Class: Mitochondria-derived peptide (MDP)
Evidence tier: Animal-only evidence
Status: Not FDA approved for any indication. Removed from FDA 503A category 2 compounding list (April 22, 2026; nomination withdrawn). FDA intends to consult PCAC July 23, 2026 regarding MOTS-c acetate and free-base forms — outcome pending. No marketing authorization in EU, UK, Canada, or Australia. No established prescription pathway in the US; sold as research chemical. Per available sources, MOTS-c falls under WADA S0 (non-approved substances); current list status not independently refreshed in this card.
Best-supported effect: AMPK-mediated improvements in insulin sensitivity, glucose tolerance, and metabolic flexibility in rodent models of diet-induced obesity and aging. Endogenous circulating MOTS-c levels correlate with insulin sensitivity and metabolic health markers in human observational studies. No controlled human efficacy trial for exogenous MOTS-c has been completed.
Main caveat: No interventional human efficacy trial for exogenous MOTS-c. Observational human data shows endogenous MOTS-c correlates with metabolic health — whether injecting synthetic MOTS-c reproduces those associations is untested. The nuclear translocation mechanism that drives much of the interesting biology may not be recapitulated by subcutaneous dosing.
What this is
MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-c) is a 16-amino-acid peptide encoded within the mitochondrial genome — specifically within the 12S ribosomal RNA gene region of mitochondrial DNA. It was discovered in 2015 by Pinchas Cohen and Changhan Lee at the USC Leonard Davis School of Gerontology and published in Cell Metabolism.
MOTS-c belongs to an emerging class of mitochondria-derived peptides (MDPs). Unlike nearly all other peptides, it is encoded in mitochondrial rather than nuclear DNA. It functions as a retrograde signal from mitochondria to the nucleus, influencing gene expression linked to metabolism and stress response. Endogenous MOTS-c levels increase with acute exercise in humans and decline with aging.
A mitochondrial DNA polymorphism in the MOTS-c coding region has been associated with type 2 diabetes risk in certain populations, suggesting MOTS-c plays a role in normal human metabolic regulation.
Chemistry
| Property | Value |
|---|---|
| Sequence | Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg (MRWQEMGYIFYPRKLR) |
| Formula | C₈₁H₁₃₂N₂₄O₂₁S₂ |
| MW | Source conflict: PE reports 2174.69 Da; RP reports 1812.2 Da. Calculated value from sequence is approximately 2172 Da, consistent with PE figure. Not independently verified in this card. |
| CAS | 1627580-64-6 |
| Length | 16 amino acids |
| Half-life | Minutes in plasma; functional effects persist hours via downstream gene expression changes |
| Origin | Encoded in mitochondrial 12S rRNA gene; endogenously produced in humans; synthetic versions available as research chemicals |
Mechanism
MOTS-c acts through several interconnected pathways described in preclinical models:
- AMPK activation via AICAR accumulation — MOTS-c inhibits the folate-methionine cycle, leading to accumulation of AICAR, an endogenous AMPK activator. AMPK activation promotes glucose uptake, fatty acid oxidation, and mitochondrial biogenesis — the same energy-sensing pathway engaged by exercise and metformin
- GLUT4 transporter upregulation — in skeletal muscle models, promotes glucose uptake through GLUT4 translocation to the cell surface, improving insulin-stimulated glucose clearance
- Nuclear translocation under metabolic stress — under oxidative or metabolic stress, MOTS-c translocates from mitochondria to the nucleus to directly regulate gene expression related to antioxidant response and metabolic adaptation; this retrograde signaling mechanism is well-characterized in cell and animal models
- Cardiolipin-adjacent stress signaling — described in source as part of the mitochondrial-stress sensing that initiates MOTS-c action
Source note: The nuclear translocation mechanism depends on intracellular MOTS-c. Whether subcutaneously injected synthetic MOTS-c reaches the relevant intracellular compartments to reproduce this mechanism is unresolved.
Evidence map
| Evidence layer | Grade | What it supports |
|---|---|---|
| Human | Observational only | Circulating MOTS-c correlates with insulin sensitivity, obesity, PCOS, cardiovascular risk, and mortality in hemodialysis patients; exercise raises endogenous MOTS-c levels; no completed interventional human trial for exogenous MOTS-c |
| Animal | Extensive | Diet-induced obesity and aging models; muscle atrophy prevention; cardiac protection; multiple organ-system models across independent research groups |
| In vitro | Strong (mechanistic) | AMPK activation via AICAR; nuclear translocation under stress; GLUT4 upregulation; folate-methionine cycle inhibition |
| Computational | None identified | — |
| Mechanism | Well-characterized | AMPK pathway is among the best-characterized metabolic signaling cascades; nuclear translocation confirmed in cell models |
CB4211 analog note: CohBar's CB4211 (NCT03998514) is a MOTS-c analog with modified pharmacokinetics, not MOTS-c itself. Phase 1b (n=20 NAFLD patients, 25 mg SC daily for 4 weeks) showed positive ALT/AST/glucose signals vs. placebo. This supports MOTS-c-derived pharmacology in humans but does not constitute evidence for MOTS-c itself.
Endogenous biomarker note: Human studies measuring circulating MOTS-c levels in response to exercise or disease are biomarker studies of endogenous peptide — they are not interventional trials of exogenous MOTS-c administration and do not directly support therapeutic claims for the administered peptide.
Claim check
| Claim | Verdict | Evidence layer | Confidence |
|---|---|---|---|
| Improves insulin sensitivity and glucose tolerance | Supported (preclinical) | Animal | High — animal; original 2015 Cell Metabolism paper and multiple independent replications |
| Endogenous MOTS-c levels rise with exercise in humans | Supported (endogenous biomarker) | Human | High — multiple human exercise studies; endogenous response, not exogenous therapy |
| Circulating MOTS-c inversely correlates with insulin resistance and metabolic disease markers | Supported (observational) | Human | Medium — consistent cross-sectional associations; causality direction not established |
| Exogenous MOTS-c improves metabolic outcomes in humans | Not established | Human | High confidence in absence — no completed interventional human trial for MOTS-c itself |
| CB4211 (MOTS-c analog) shows metabolic signal in NAFLD | Weak | Human | Low — n=20, Phase 1b, different molecule, Phase 2 never ran; analog, not MOTS-c |
| MOTS-c reverses aging in humans | Contradicted | None | High — mouse aging data only; no human trial evidence; published literature explicitly contradicts this framing |
Experimental exposure
No controlled human efficacy trial for exogenous MOTS-c has been completed. Key animal and analog human data from the available literature:
| Study context | Population / model | Exposure | Endpoint / outcome | Reference |
|---|---|---|---|---|
| Diet-induced obesity model | Adult mice on high-fat diet | MOTS-c injection; IP | Improved glucose tolerance, insulin sensitivity, reduced fat mass | |
| Late-life aging model | Mice aged 22–23 months | MOTS-c SC injection 3×/week | Improved treadmill performance, metabolic flexibility, skeletal muscle function | |
| CB4211 Phase 1b (MOTS-c analog, not MOTS-c) | n=20 obese NAFLD patients | CB4211 25 mg SC daily, 4 weeks | Statistically significant reduction in ALT, AST, glucose vs. placebo; trend toward weight reduction; persistent injection-site reactions as primary AE | NCT03998514 |
The first-in-human trial of MOTS-c itself (NCT07505745; insulin sensitivity indication) was registered in 2025. No results available at time of source compilation.
Safety signals
Human safety data for MOTS-c itself: None. No clinical safety trial for MOTS-c has been completed.
CB4211 Phase 1a (analog): 65 healthy volunteers; persistent injection-site reactions reported as the primary adverse event; no serious adverse events described in source.
Theoretical — additive hypoglycemia: MOTS-c activates AMPK and improves insulin-stimulated glucose uptake. Source describes theoretical additive hypoglycemia risk with insulin, sulfonylureas, meglitinides, and metformin. No controlled interaction data in humans.
Research-chemical quality concern: Source notes synthetic MOTS-c sold through research-chemical channels varies in purity, peptide identity, and endotoxin contamination. 16-amino-acid synthesis complexity increases contamination risk relative to shorter peptides.
Unknown long-term effects: Chronic exogenous AMPK activation has not been studied at any dose or duration in humans. Source flags this explicitly.
Regulatory status
| Jurisdiction | Status |
|---|---|
| US (FDA) | Not approved. Removed from 503A category 2 (April 22, 2026; nomination withdrawn). FDA intends to consult PCAC July 23, 2026 re: MOTS-c acetate and free base. No compounding authorization pending PCAC outcome. No prescription pathway. [FDA 503A doc] |
| EU (EMA) | No marketing authorization |
| UK (MHRA) | No license |
| Canada | No approval; investigational only |
| Australia (TGA) | No approval; general enforcement action taken against unapproved peptide sales |
| WADA | per available sources as prohibited under S0 (non-approved substances for human therapeutic use); current list status not independently refreshed in this card |
Clinical trials
| Trial | Design | Indication | Status | Reference |
|---|---|---|---|---|
| CB4211 Phase 1a/1b (CohBar) — MOTS-c analog, not MOTS-c | Phase 1a: 65 healthy volunteers (safety/dosing). Phase 1b: n=20 obese NAFLD patients, 25 mg SC daily, 4 weeks | NASH/NAFLD (analog) | Completed 2021; CohBar wound down 2023; Phase 2 never ran | NCT03998514 |
| NCT07505745 — first MOTS-c human trial | Interventional; insulin sensitivity | Insulin resistance | Registered 2025; not yet complete | NCT07505745 |
Community patterns
This section describes reported off-label use patterns from the available literature. These are not clinically validated protocols.
| Pattern | Evidence quality | Notes |
|---|---|---|
| Subcutaneous injection for exercise performance and metabolic support | Anecdotal; source-aggregated community reports | Source notes community use is "almost entirely subcutaneous injection" with reported effects clustering around endurance, recovery, and body composition over extended use; uncontrolled, not a clinical dataset |
published literature explicitly notes that community users tend to stack MOTS-c with exercise rather than replace it, and that the community use pattern corresponds directionally to the animal model signal. per available sources community route (subcutaneous injection) is not supported by completed human evidence for any indication.
Open questions
From the available literature:
- Human pharmacokinetics — absorption, distribution, half-life, and tissue uptake of exogenous MOTS-c have not been characterized in humans at any dose or route
- Nuclear translocation recapitulation — the mitochondria-to-nucleus translocation mechanism that drives much of the interesting biology may not be recapitulated by subcutaneous dosing; whether injected synthetic MOTS-c reaches the intracellular compartments relevant to its mechanism is unresolved
- Translation of observational signals — human observational data links endogenous MOTS-c levels to metabolic health, but whether raising levels through exogenous dosing reproduces the protective associations is untested
- CB4211 vs MOTS-c pharmacological equivalence — CB4211 has modified pharmacokinetics; its Phase 1b signal may or may not generalize to the parent molecule
- Long-term safety — chronic exogenous AMPK activation has not been studied in humans
- Dose-ranging — no controlled trial has identified minimum effective or maximum tolerated human doses
▸3-letter notation
▸citationbibtex
@peptide{pep00003,
sequence = {MRWQEMGYIFYPRKLR},
target = {longevity},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}