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MOTS-c

From PeptidePlaza, the free peptide reference · Entry #008 · Metabolic · Hand-curated entry · Editorial standards

Research warning. MOTS-c is an experimental mitochondrial peptide. No human clinical trials for obesity or metabolic syndrome have been completed. For in-vitro and in-vivo animal research use only.

MOTS-c (also known as Mitochondrial-Derived Peptide, MDP) is a metabolic research peptide. A 16-amino acid peptide encoded within the mitochondrial genome — a newly discovered class of signaling molecule. Regulates metabolic homeostasis via AMPK and FOXO1 pathways.

MOTS-c is a 16-amino acid mitochondrial-derived peptide (MDP) encoded in the 12S rRNA region of the mitochondrial genome — making it one of a small class of peptides with mitochondrial DNA origin. It translocates from mitochondria to the nucleus in response to metabolic stress, directly activating AMPK (AMP-activated protein kinase) and FOXO1, regulating glucose and lipid metabolism. Research in mice shows improved insulin sensitivity, exercise capacity, and reversal of diet-induced obesity and high-fat diet metabolic dysfunction. MOTS-c levels decline with age, suggesting potential roles in metabolic aging.

1 Mechanism of action

Translocates from mitochondria to nucleus under metabolic stress. Activates AMPK and FOXO1, increasing glucose uptake, fatty acid oxidation, and mitochondrial biogenesis. Reduces ROS and inflammatory signaling.

Primary targets: AMPK (indirect) · FOXO1 (transcription factor)

2 Reported effects

Effects below are those reported in the published literature cited on this page. They are not claims of clinical benefit and not medical advice.

2.1 Reported benefits

  • Mimics the metabolic effects of exercise via AMPK activation
  • Improves cellular insulin sensitivity and glucose uptake
  • Promotes fatty acid oxidation and prevents diet-induced obesity
  • Protects against age-related metabolic decline

2.2 Side effects

  • Potential hypoglycemia in fasted states
  • Injection site irritation
  • Long-term human side effects remain unknown due to lack of RCTs
  • Unknown interactions with mitochondrial disorders

3 Chemical and physical properties

CAS number1448498-00-7
Molar mass2174.58 g/mol
Purity (typical)>98.5%
Half-life~30 min–2 hours (estimated)
Storage−20 °C, lyophilised powder, desiccated
SolubilitySterile water / bacteriostatic water
Receptors / targetsAMPK (indirect), FOXO1 (transcription factor)

3.1 Amino acid sequence

MRWQEMGYIFYPRKLR

4 Research dosages

5–15 mg SC 2–3x weekly in preclinical protocols; human-equivalent dose unknown.

Dosages are reported from published protocols for reference only. Research chemicals are not for human consumption.

5 Research studies (8)

  1. The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis
    Cell Metabolism (2015) · Preclinical · N=80 (mice)
    Discovery paper. MOTS-c identified as a mitochondria-encoded peptide that activates AMPK, improves insulin sensitivity, and reverses diet-induced obesity in mice.
    Key finding: MOTS-c reversed high-fat-diet-induced obesity and insulin resistance by activating AMPK — a novel mitochondria-to-nucleus signaling pathway.
  2. MOTS-c as an Exercise Mimetic: Systemic Metabolic Effects
    Nature Communications (2021) · Preclinical · N=120 (mice)
    MOTS-c injected into aged mice restored exercise capacity and metabolic function; regulates AICAR pathway similar to physical activity.
    Key finding: MOTS-c restored running endurance in aged mice to young-adult levels — exercise-mimetic effects confirmed via AMPK and AICAR pathways.
  3. Mitochondrial-derived peptide MOTS-c activates metabolic signaling but blunts reparative function in human mesenchymal stromal cells
    Inflammation and regeneration (2026) · Preclinical
    These results suggest a dissociation between metabolic activation and functional stemness, underscoring context-dependent effects of mitochondrial-derived peptides in MSC biology.
  4. Mitochondrial peptide MOTS-c suppresses systemic and cardiac inflammasome activation in a diabetic rat model
    Experimental physiology (2026) · Preclinical
    Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.
  5. Reduced Circulating MOTS-c Levels in Hashimoto's Thyroiditis Reflect Integrated Autoimmune and Metabolic Dysregulation: A Cross-Sectional Study
    Journal of clinical medicine (2026) · Preclinical · n=180
    Circulating MOTS-c levels are markedly reduced in patients with HT and are independently associated with insulin resistance and autoimmune burden.
  6. MOTS-c partially protects against skeletal muscle deterioration in C26 cachexia
    Frontiers in medicine (2026) · Preclinical
    Our findings demonstrate that MOTS-c partially protects against skeletal muscle loss in C26 cachexia by modulating FOXO-driven catabolic signaling and promoting mitochondrial biogenesis, supporting its therapeutic potential in cancer cachexia.
  7. MOTS-c: How a secreted mitochondrial microprotein may become a potential treatment for inflammatory lung diseases
    Journal of translational medicine (2026) · Preclinical
    Current evidence positions MOTS-c as a promising biomarker and potential therapeutic candidate in respiratory medicine.
  8. MOTS-c preserves mitochondrial subpopulation bioenergetics and genome integrity to attenuate cardiac ischemia reperfusion injury
    Molecular biology reports (2026) · Preclinical
    MOTS-c treatment was associated with preservation of mitochondrial functional integrity and improved cardiac recovery following IR injury.

6 Safety and risk profile

6.1 Regulatory status

MOTS-c is currently classified as Investigational. It has no approved human indication in the United States; availability elsewhere does not imply demonstrated safety or efficacy.

Safety score: 35/100 — high concern. Derived from clinical data volume, known risks and regulatory status.

6.2 Contraindications

Conditions and populations in which use is contraindicated:

  • Known mitochondrial disorders (e.g., MELAS, LHON)
  • Hypoglycemia-prone conditions
  • Pregnancy (no reproductive safety data)
  • Use with other AMPK activators (e.g., metformin) — additive risk

6.3 Drug interactions

Drug or classInteractionRisk
Metformin / berberineBoth activate AMPK — additive hypoglycemic effect possible.Moderate
Insulin / sulfonylureasMOTS-c enhances insulin sensitivity — hypoglycemia risk in diabetic models.High

6.4 Long-term risks

  • Mitochondrial hormesis disruption with chronic AMPK over-activation
  • Unknown effects on cancer metabolism (AMPK is a double-edged sword in oncology)
  • Potential for excessive mitochondrial uncoupling and energy wasting
  • No human safety data beyond anecdotal use

6.5 Research best practices

  • Store lyophilized at −20 °C; avoid repeated freeze-thaw
  • Monitor blood glucose in fasted-state protocols
  • Use within 30 days of reconstitution (refrigerated)
  • Best administered fasted to maximize AMPK activation
Safety data disclaimer. Safety assessments are based on published literature and are for educational reference only. Clinical evidence varies significantly between peptides. Always consult primary research and current regulatory guidance.

7 Frequently asked questions

How do researchers use MOTS-c?
In research settings, MOTS-c is primarily used as an "exercise mimetic". It is administered to study cellular endurance, mitochondrial repair, and the reversal of age-related metabolic decline without requiring physical exertion from the subject.
Does it actually replace exercise?
On a cellular level, MOTS-c activates the AMPK pathway—the exact same chemical pathway that your body triggers during intense cardiovascular exercise. This forces cells to take up glucose and burn fat at a heightened rate.
What results have been seen in animal models?
In rodent studies, mice given MOTS-c experienced completely reversed diet-induced obesity, significantly improved running endurance, and prevented age-dependent insulin resistance compared to control groups.

8 References

  1. Mitochondrial-derived peptide MOTS-c activates metabolic signaling but blunts reparative function in human mesenchymal stromal cells PubMed (2026). Xing L, et al.. View source
  2. Mitochondrial peptide MOTS-c suppresses systemic and cardiac inflammasome activation in a diabetic rat model PubMed (2026). Mills AR, et al.. View source
  3. Reduced Circulating MOTS-c Levels in Hashimoto's Thyroiditis Reflect Integrated Autoimmune and Metabolic Dysregulation: A Cross-Sectional Study PubMed (2026). Sonay HO, et al.. View source
  4. MOTS-c partially protects against skeletal muscle deterioration in C26 cachexia PubMed (2026). Jamnick NA, et al.. View source

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9 See also

For research reference only. Not medical advice. Peptides may be regulated or restricted in your jurisdiction. Entry validated by the PeptidePlaza Biomedical Research Desk; see editorial standards.

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