MOTS-c
Mitochondrial-Derived Peptide for Metabolic Homeostasis & Longevity
MOTS-c — Mitochondrial Open Reading Frame of the 12S rRNA-c
Last reviewed: March 2026
What is MOTS-c?
MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c) is a 16-amino-acid peptide encoded within the mitochondrial genome — one of the only peptides known to be encoded by mitochondrial DNA. It regulates metabolic homeostasis, insulin sensitivity, and exercise capacity by activating AMPK signaling. Circulating MOTS-c levels decline with age, and higher levels have been found in centenarians.
Molecular Composition
MOTS-c is a 16-amino-acid peptide (MRWQEMGYIFYPRKLR) encoded within the 12S rRNA gene of the mitochondrial genome. Unlike nuclear-encoded peptides, MOTS-c is translated in the mitochondrial matrix and can translocate to the nucleus under metabolic stress, directly regulating gene expression.
How Does It Work?
MOTS-c mimics the metabolic effects of exercise by activating AMPK in skeletal muscle and liver, increasing glucose uptake and fatty acid oxidation.
MOTS-c activates AMP-activated protein kinase (AMPK) in skeletal muscle and liver, mimicking the metabolic effects of exercise and caloric restriction. It also regulates the folate cycle and one-carbon metabolism, affecting nucleotide synthesis, methylation reactions, and redox balance. Under metabolic stress, MOTS-c translocates to the nucleus where it regulates stress-response genes.
MOTS-c is a peptide encoded in mitochondrial DNA that acts as a metabolic master regulator, activating AMPK to improve insulin sensitivity, increase fat burning, and promote longevity pathways. It was discovered in 2015 and found at higher levels in centenarians.
MOTS-c activates AMPK in muscle and liver, producing effects similar to intense exercise: increased glucose uptake, enhanced fat oxidation, and improved insulin sensitivity.
MOTS-c levels decline with age and obesity. Its discovery in centenarians at higher levels than in younger adults suggests it may be a key mediator of exceptional longevity.
MOTS-c is a mitochondrial-derived peptide that activates AMPK to mimic the metabolic effects of exercise, with declining levels linked to aging and metabolic disease.
Key Research Pathways
AMPK Activation / Metabolic Homeostasis
Activates AMP-activated protein kinase (AMPK) in skeletal muscle and liver, mimicking the metabolic effects of exercise and caloric restriction.
Folate Cycle / One-Carbon Metabolism
Regulates the folate cycle and one-carbon metabolism, affecting nucleotide synthesis, methylation reactions, and redox balance.
Insulin Sensitization
Improves insulin sensitivity in skeletal muscle by activating AMPK-dependent glucose transporter (GLUT4) translocation, independent of insulin signaling.
Key Findings from the Literature
- Discovered by Changhan David Lee at USC; published in Cell Metabolism (2015)
- Higher circulating MOTS-c levels found in centenarians vs. younger adults (Nature Communications, 2021)
- Activates AMPK to improve insulin sensitivity and increase fat oxidation
- Regulates folate cycle and one-carbon metabolism
- Translocates to the nucleus under metabolic stress to regulate gene expression
Evidence by Claimed Outcome
Each outcome rated by the highest level of evidence available. Tiers follow our 5-tier methodology.
Study counts reflect peer-reviewed publications in the evidence database below. "Theoretical" outcomes have mechanistic rationale only. Learn about our evidence tiers →
Structured Evidence Table
1 cited study — model, sample size, outcome, and effect size from published literature.
| Study | Model | Sample | Outcome | Effect Size | Level |
|---|---|---|---|---|---|
Lee C, et al. (2015) The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and redu… PubMed | Rodent (mouse) — diet-induced obesity | n=40 | Reduced body weight, improved insulin sensitivity, and AMPK activation | Body weight reduction: ~15% vs. control; insulin sensitivity: ~2× improvement | Animal |
Pharmacokinetics
MOTS-c — absorption, distribution, metabolism, and excretion data
| Parameter | Value | Source |
|---|---|---|
| Half-Life (t½) | ~1–2 hours (estimated) Preclinical data; no human PK studies | Preclinical Data |
| Time to Peak (Tmax) | ~30–60 minutes Preclinical estimates | Preclinical Data |
| Bioavailability (F) | Estimated 60–80% (SC/IM) No published human bioavailability data | Preclinical Data |
| Onset of Action | Hours to days AMPK activation and metabolic effects | — |
| Duration of Action | Variable Metabolic effects persist beyond plasma half-life | — |
Mitochondria-derived peptide encoded in the 12S rRNA gene. Activates AMPK and improves insulin sensitivity. Endogenous levels decline with age. Research-stage only; no clinical trials completed.
References:
• Lee C et al. Cell Metab 2015
• Kim KH et al. Nat Commun 2018
Important Research Context
MOTS-c
Longevity Research
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Technical Specifications
| Peptide Class | Mitochondrial-derived peptide (16 amino acids) |
| Molecular Weight | 2,174.5 Da |
| Regulatory Status | Research chemical; no clinical approval |
| Available Sizes | 5mg, 10mg vials |
| Form | Lyophilized powder |
| Purity | ≥99% (third-party tested) |
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Known Interactions
5 documented interactions for MOTS-c
Both target cellular aging pathways via different mechanisms — Epithalon via telomerase, MOTS-c via AMPK/mitochondrial function.
Interaction data is based on published research, known pharmacological mechanisms, and clinical practitioner experience. Evidence tiers: Clinical = human data; Emerging = preclinical/case reports; Theoretical = mechanism-based inference. Always consult a qualified healthcare provider before combining compounds.
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Other Compounds in This Guide
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