MOTS-c
Mitochondria-Derived PeptideresearchAlso known as: Mitochondrial Open Reading Frame of the 12S rRNA Type-c, Mitochondrial-Derived Peptide MOTS-c
A mitochondria-derived peptide that acts as an exercise mimetic, improving metabolic health, insulin sensitivity, and physical performance through AMPK activation.
Overview
MOTS-c is a 16-amino acid peptide encoded by the mitochondrial genome (within the 12S rRNA gene). Discovered in 2015 by Pinchas Cohen's lab at USC, MOTS-c is considered a mitochondrial-derived peptide (MDP) that acts as a signaling molecule between mitochondria and the nucleus (retrograde signaling). Its most striking property is functioning as an exercise mimetic — activating many of the same metabolic pathways triggered by physical exercise, particularly AMPK. MOTS-c improves glucose metabolism, enhances insulin sensitivity, prevents age-related metabolic decline, and has been shown to improve physical performance in aged mice. Notably, MOTS-c translocates to the nucleus under metabolic stress and directly regulates gene expression. Its levels decline with age, and a naturally occurring variant (m.1382A>C) is enriched in Japanese centenarians, linking it to exceptional longevity.
Mechanism of Action
MOTS-c operates through several interconnected pathways: (1) Activates AMPK (AMP-activated protein kinase), the master metabolic sensor, mimicking exercise signaling; (2) Inhibits the folate-methionine cycle, altering cellular one-carbon metabolism and purine biosynthesis; (3) Translocates to the nucleus under metabolic stress, directly regulating adaptive gene expression via interaction with the antioxidant response element (ARE); (4) Enhances skeletal muscle glucose uptake independently of insulin; (5) Promotes fatty acid oxidation and mitochondrial biogenesis; (6) Reduces age-related inflammation through NF-κB pathway modulation; (7) Improves endothelial function and reduces atherosclerosis development.
Molecular Formula
C101H152N28O22S2
Molecular Weight
2174.6 g/mol
Sequence
Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg
Dosage Protocols
Dose Range
5mg – 10mg
Frequency
3-5 times per week
Route
subcutaneous
Cycle Length
4-8 weeks (experimental)
No established human dosing. Mouse studies use 5-15mg/kg IP. Human biohacking protocols extrapolate much lower doses. Often cycled to match exercise schedules. Morning administration may best mimic exercise timing.
Source: Preclinical research extrapolation
Side Effects
| Effect | Severity |
|---|---|
| Unknown human side effects | unknown |
| Injection site irritation | mild |
| Potential hypoglycemia | mild |
| GI discomfort | mild |
Pros & Cons
Functions as an exercise mimetic, activating AMPK and metabolic pathways normally triggered by physical activity
Natural variant linked to exceptional longevity in Japanese centenarians
Endogenously produced peptide with fundamental roles in mitochondrial-nuclear communication
Demonstrated restoration of physical performance in aged mice, suggesting genuine anti-aging potential
Multi-target metabolic benefits: insulin sensitivity, fat oxidation, and glucose uptake
No human clinical trials — entirely preclinical evidence
Human dosing, pharmacokinetics, and safety profile are unknown
Relatively expensive as a research peptide due to limited commercial availability
Effects on one-carbon metabolism and folate cycle raise theoretical concerns about long-term supplementation
Research Studies
Legal Status
Not approved by any regulatory agency. Available as a research peptide. No human clinical trials completed. Investigational compound for metabolic disease and aging.
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