MOTS-c

The Mitochondrial Exercise Mimetic

MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-c) is a 16-amino acid peptide encoded by the mitochondrial genome, discovered in 2015 by Dr. Changhan Lee's laboratory. This peptide represents a paradigm shift in understanding mitochondrial function—demonstrating that mitochondria actively regulate metabolism through encoded signaling peptides.

MOTS-c is the first mitochondrial-derived peptide (MDP) to reach clinical investigation, with ongoing studies exploring its potential in metabolic diseases and aging.

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Why Mitochondrial Signaling Matters

MOTS-c exemplifies a new class of mitochondrial regulators:

Mechanism	Action	Metabolic Effect
AMPK Activation	Energy sensor engagement	Enhanced glucose uptake
Nuclear Translocation	Stress-responsive gene regulation	Adaptive metabolism
Folate-AICAR Pathway	De novo purine synthesis inhibition	Metabolic flexibility
Exercise Response	Upregulated by physical activity	Endurance enhancement

MOTS-c levels decline with age, correlating with decreased metabolic flexibility and physical capacity.

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Research Focus Areas

MOTS-c is being studied for its potential effects on:

• Insulin sensitivity — skeletal muscle glucose metabolism
• Exercise capacity — endurance and physical performance in aged models
• Obesity — prevention of diet-induced weight gain
• Aging — reversal of age-related metabolic decline
• Cardiovascular function — cardiac protection via AMPK pathway
• β-cell senescence — diabetes prevention mechanisms
• Stress adaptation — antioxidant response element (ARE) gene activation
• Muscle homeostasis — sarcopenia prevention

Clinical trials are investigating MOTS-c in obesity and fatty liver disease (NCT03998514).

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Clinical Development Context

• Discovery: 2015 (Lee laboratory, USC)
• Phase: Clinical trials ongoing
• Developer: CohBar, Inc. (initial development)
• Trial registry: NCT03998514 (obesity/fatty liver)
• Regulatory status: Investigational; WADA prohibited substance

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Technical Specifications

• Synonyms: Mitochondrial ORF of the 12S rRNA-c
• Class: Mitochondrial-derived peptide (MDP)
• Sequence: MRWQEMGYIFYPRKLR
• Molecular Weight: ~2,174 g/mol
• Form: Sterile lyophilized powder
• Encoding region: Mitochondrial 12S rRNA gene

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Storage & Handling

• Lyophilized: Store at -20°C
• Reconstituted: Store at 2–8°C
• Protect from light and moisture
• Avoid repeated freeze-thaw cycles

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