MOTS-c
Mitochondrial-Derived Peptide · Metabolic Regulator
MOTS-c is a mitochondrial-derived peptide that operates as a mitohormone through the Folate-AICAR-AMPK pathway. Under metabolic stress, it translocates to the nucleus to bind stress-response transcription factors (NRF2, ATF1/ATF7), regulating genes involved in metabolism and cellular adaptation.
Overview
MOTS-c is a mitochondrial-derived peptide that operates as a mitohormone through the Folate-AICAR-AMPK pathway. Under metabolic stress, it translocates to the nucleus to bind stress-response transcription factors (NRF2, ATF1/ATF7), regulating genes involved in metabolism and cellular adaptation.
Inhibits the folate cycle leading to AMPK activation. Under metabolic stress, translocates to nucleus to bind stress-response transcription factors, regulating genes involved in metabolism, insulin sensitivity, and cellular adaptation.
Research indications
What the compound has been studied for, grouped by body system. Effect size is the reported magnitude where it was measured — not a recommendation.
Improves insulin sensitivity by ~30% in animal studies through AMPK activation.
Restores metabolic function via insulin receptor sensitization.
Promotes fatty acid oxidation despite identical caloric intake.
Reverses age-dependent physical decline in animal models.
Enhances mitochondrial function via PGC-1α activation.
6.4% median lifespan extension observed in mice studies.
12-15% improvement in running performance from single dose in studies.
Exercise induced 11.9-fold increase in skeletal muscle MOTS-c.
Supports muscle recovery and adaptation to exercise.
A large effect in a weak study and a small effect in a strong one are different things. Effect size is never evidence of use in people.
- Class
- Mitochondrial-derived peptide (MDP)
- Chain length
- 16 residues
- Molecular weight
- 2174.6 Da
- Half-life
- ~30 min
- Typical dose
- Start 5mg daily, increase to 10-15mg based on goals
- Frequency
- Daily for metabolic support, or 3x weekly for anti-aging
- Cycle length
- 4-12 weeks depending on goals
- Storage
- Refrigerate reconstituted solution at 2-8°C, use within 14 days
Molecular data
- Type
- Mitochondrial-derived peptide (MDP)
- Molecular weight
- 2174.6 Da
- Chain length
- 16 residues
- Half-life
- 30 min
MRWQEMGYIFYPRKLRDosing reference
Doses reported in the literature and by suppliers. These are a record of what has been used in research — reference, never instruction.
| Context | Route | Amount | Frequency |
|---|---|---|---|
| Metabolic health | SubQ | 5-10mg | Once daily |
| Anti-aging protocol | SubQ | 15mg | 3x weekly |
| Exercise performance | SubQ | 10-15mg | Pre-workout |
| Conservative start | SubQ | 5mg | Once daily |
Interactions
Both activate AMPK; monitor for additive hypoglycemic effects.
Complementary mitochondrial enhancement through different pathways.
Different mechanisms allow safe combination.
Both are AMPK activators; monitor for additive effects.
Complementary SIRT1/AMPK activation pathways.
May require dose adjustments to prevent hypoglycemia.
Quality checklist
- ✓White to off-white powder with uniform appearance indicating proper storage
- ✓Clear, colorless solution without particles after reconstitution
- ✓Sequence verification (MRWQEMGYIFYPRKLR) with CoA >95% purity by RP-HPLC
- !Limited human clinical data - start conservatively
- !WADA banned substance - not for competitive athletes
- ×Discolored powder or solution
- ×Cloudy solution after reconstitution
- ×No certificate of analysis available
What to expect
Safety
- Generally well-tolerated in animal studies with minimal side effects
- Mild injection site reactions (redness, swelling)
- Severe allergic reactions or anaphylaxis
- Recurrent hypoglycemia (<50 mg/dL)
- Persistent severe injection site reactions
- Unexplained weight loss >10% of baseline
- Pregnancy or breastfeeding
- WADA prohibited substance (banned for athletic competition)
- Limited long-term human safety data
FAQ
How does MOTS-c help with insulin resistance?
MOTS-c activates AMPK, a cellular energy sensor that improves insulin sensitivity by approximately 30% in animal studies. It works through the Folate-AICAR-AMPK pathway, enhancing glucose uptake in muscle tissue. This addresses metabolic dysfunction at the mitochondrial level.
Does MOTS-c work for weight loss?
Indirectly. MOTS-c promotes fatty acid oxidation despite identical caloric intake, improving metabolic flexibility. Combined with exercise and diet, it enhances the body's ability to burn fat for fuel. It's not a direct weight-loss peptide like GLP-1 agonists, but supports metabolic health.
Can MOTS-c extend lifespan in humans?
Unknown in humans. Animal studies show 6.4% median lifespan extension in mice. MOTS-c clearly supports healthspan and metabolic optimization, but human longevity data doesn't exist. It's a longevity-supporting compound, not a proven life-extension drug.
Should I take MOTS-c before or after exercise?
Morning before exercise is optimal. MOTS-c activates AMPK within 30 minutes, enhancing exercise performance by 12-15% in studies. Post-workout benefits are also seen for recovery. However, pre-exercise timing maximizes the performance enhancement during the workout itself.
References
- 1The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin ResistanceLee, C., et al. · Cell Metabolism · 2015
Landmark discovery paper identifying MOTS-c as a 16-amino-acid peptide encoded by mitochondrial DNA. Prevented age-dependent and high-fat-diet-induced insulin resistance and obesity in mice via AMPK activation in skeletal muscle.
animalPubMed 25738453 ↗ - 2The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic StressKim, S.J., et al. · Cell Metabolism · 2018
MOTS-c rapidly translocates to the nucleus within 30 minutes under metabolic stress in an AMPK-dependent manner, where it interacts with stress-responsive transcription factors including NRF2 and ATF7 to regulate nuclear gene expression.
reviewPubMed 29983246 ↗ - 3MOTS-c Is an Exercise-Induced Mitochondrial-Encoded Regulator of Age-Dependent Physical Decline and Muscle HomeostasisReynolds, J.C., et al. · Nature Communications · 2021
Exercise induced an 11.9-fold increase in skeletal muscle MOTS-c. MOTS-c enhanced physical performance across age groups and improved muscle homeostasis in aging mice.
animalPubMed 33473109 ↗ - 4MOTS-c Increases in Skeletal Muscle Following Long-Term Physical Activity and Improves Acute Exercise Performance After a Single DoseHyatt, J.K. · Physiological Reports · 2022
4-8 weeks of voluntary running increased MOTS-c protein expression ~1.5-5-fold in rodent skeletal muscles, sustained for 4-6 weeks of detraining. Single dose improved acute exercise performance.
animalPubMed 35808870 ↗ - 5The Mitochondrial-Derived Peptide MOTS-c Relieves Hyperglycemia and Insulin Resistance in Gestational Diabetes MellitusYin, Y., et al. · Pharmacological Research · 2022
MOTS-c significantly alleviated hyperglycemia, improved insulin sensitivity and glucose tolerance, and reduced birth weight and offspring death in a gestational diabetes mouse model.
animalPubMed 34798268 ↗