MOTS-c (40mg)

What Is MOTS-c and What Does It Do?

MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c) is a mitochondrial-derived peptide composed of 16 amino acids. It plays a key role in cellular metabolism, particularly in regulating glucose uptake, insulin sensitivity, and energy homeostasis.

Emerging research suggests that MOTS-c may influence exercise capacity, mitochondrial function, and stress resistance, making it a promising subject in studies on metabolic disorders, aging, and longevity.

Observed Effects of MOTS-c in Preclinical Metabolic Studies

In preclinical studies, MOTS-c has demonstrated a range of promising effects related to metabolic regulation and cellular energy balance.

Animal models have shown that MOTS-c may enhance insulin sensitivity, promote glucose utilization in skeletal muscle, and reduce diet-induced obesity. These effects appear to be mediated through activation of AMPK (AMP-activated protein kinase) and other metabolic signaling pathways.

Additionally, MOTS-c has been observed to improve exercise tolerance, increase mitochondrial efficiency, and contribute to stress resistance at the cellular level, particularly under metabolic or oxidative stress conditions. Researchers are actively investigating its potential role in combating age-related decline, metabolic syndrome, and mitochondrial dysfunction.

These findings underscore MOTS-c’s growing relevance in experimental models of aging, obesity, and metabolic disease. However, like all research peptides, MOTS-c is strictly in the preclinical phase and is not approved by the FDA for human use.

MOTS-c Mechanism of Action

MOTS‑c exerts its effects through a sophisticated mechanism centered around AMP‑activated protein kinase (AMPK)—a crucial energy sensor that regulates metabolism, mitochondrial function, and cellular resilience.

Key mechanisms activated by MOTS‑c include:

• AMPK activation via folate cycle disruption and AICAR accumulation
  
• Enhanced mitochondrial biogenesis (via PGC‑1α phosphorylation)
  
• Increased fatty acid oxidation and reduced fat accumulation
  
• Suppressed inflammation and pain signaling in neurons
  
• Nuclear translocation to regulate stress-response genes (e.g., NRF2, ATF1)

Activation of AMPK via Folate Pathway Modulation

MOTS‑c disrupts the folate-methionine cycle, causing an accumulation of AICAR (5‑aminoimidazole‑4‑carboxamide ribonucleotide), a known AMPK activator. Elevated AICAR mimics AMP and stimulates AMPK, leading to downstream metabolic benefits such as enhanced fatty acid oxidation and glucose uptake.

Enhancing Mitochondrial Biogenesis through AMPK–PGC‑1α

Once activated, AMPK triggers phosphorylation of PGC‑1α, a master regulator of mitochondrial biogenesis. This cascade promotes increased mitochondrial content and function, an effect observed in muscle tissue, liver, bone, and nerve tissue in preclinical models.

Modulating Lipid Metabolism & Reducing Fat Accumulation

MOTS‑c promotes fatty acid oxidation by stimulating β‑oxidation enzymes and reducing lipid accumulation in muscle and liver tissues. This effect is mediated through AMPK-induced activation of ACC (acetyl-CoA carboxylase) and CPT‑1, resulting in reduced adiposity and inflammation.

Anti-Inflammatory & Pain-Reducing Effects via AMPK

MOTS‑c suppresses inflammatory signaling in microglia and sensory neurons by activating AMPK and inhibiting MAPK pathways. These anti-inflammatory and antinociceptive effects have been observed in neuropathic and inflammatory pain models—and are blocked when AMPK is inhibited. 

In other words, when MOTS‑c levels drop in mice with nerve injury, administering MOTS‑c reverses pain behaviors by activating AMPK in the spinal cord—this reduces microglial-driven inflammation and neuronal oxidative stress, but crucially does not involve opioid receptors..

This means MOTS‑c provides analgesic relief via a non-opioid, inflammation-modulating pathway. It boosts AMPK activity in spinal neurons, suppresses pro-inflammatory cytokines, and protects against oxidative neuronal damage—all while avoiding typical opioid-related side effects and tolerance issues, making it an intriguing candidate for future neuropathic pain research.

Nuclear Translocation & Stress-Responsive Gene Regulation

Under cellular stress, MOTS‑c can translocate to the nucleus—a process that depends on AMPK activity. Once inside, it binds to chromatin and influences expression of stress-response genes such as ATF1 and NRF2, helping cells adapt to metabolic and oxidative stress.

Under metabolic stress, such as glucose deprivation or oxidative agents, MOTS‑c quickly moves into the nucleus (in around 30 minutes) to directly regulate gene expression in an AMPK-dependent way.

Once inside, it binds to antioxidant response element (ARE)-containing promoter regions and interacts with transcription factors like NRF2 and ATF1, which boost cellular protective responses.

This form of mitonuclear communication enhances the expression of genes involved in stress resistance and metabolic homeostasis, effectively allowing cells to adapt to and survive challenging conditions.

MOTS‑c Research Applications

MOTS‑c is gaining momentum in research for its promising roles across metabolism, exercise, and aging research.

Metabolic Health & Insulin Resistance

MOTS‑c improves insulin sensitivity and glucose metabolism via AMPK activation in skeletal muscle. In mice fed a high-fat diet, MOTS‑c treatment reversed insulin resistance, enhanced GLUT4-mediated glucose uptake, and reduced obesity-related inflammation.

Clinical research has shown that circulating MOTS‑c levels are significantly lower in individuals with obesity and type 2 diabetes, suggesting a potential role for MOTS‑c deficiency in the pathogenesis of metabolic dysfunction. 

Exercise Enhancement & Healthspan

Animal studies demonstrate that MOTS‑c boosts physical performance at any age in both mice and humans. In particular, MOTS‑c has been shown to mimic exercise-like effects.

In one study, MOTS‑c treatment enhanced physical capacity and induced metabolic gene expression similar to that triggered by exercise when administered to mice of various ages.

In humans, acute high-intensity exercise led to a marked increase in MOTS‑c levels, rising approximately 11.9-fold in skeletal muscle and 1.5-fold in plasma, underscoring its role as an exercise-induced mitochondrial peptide.

Aging & Longevity

MOTS‑c levels decline with age, and variants in humans are associated with exceptional longevity. In mice, MOTS‑c treatment improves metabolic flexibility and counters age-related insulin resistance, positioning it as a candidate in healthy-aging research.

Bone Health & Remodeling

Recent studies reveal MOTS‑c as a regulator of bone metabolism, thus enhancing bone formation and suppressing osteoclast activity in response to mechanical stimuli.

Cardiovascular & Liver Protection

Emerging evidence suggests MOTS‑c protects against liver steatosis in NASH models by reducing apoptosis and boosting metabolic signaling. Concurrent benefits are observed in cardiovascular function and inflammation modulation.

Immunomodulation & Anti‑inflammation

MOTS‑c elevates anti-inflammatory cytokines (e.g., IL‑10), suppresses STAT3 signaling, and reduces proinflammatory markers, suggesting a role in immune regulation and systemic inflammation reduction.

Oncological Biomarkers & Tumor Biology

Although still exploratory, MOTS‑c is investigated as a biomarker in adrenal and other tumors: decreased local expression but increased serum levels correlate with tumor type and progression, indicating the peptide’s diagnostic potential in oncology.

MOTS‑c – Peptide Characteristics

• Molecular Formula: C₁₀₁H₁₅₂N₂₈O₂₂S₂
• CAS Number: 1627580‑64‑6
• Amino Acid Sequence: MRWQEMGYIFYPRKLR
• Synonyms: MOTS‑10
• Molar Mass: 2,174.64 g/mol
• Storage Recommendations: 
  • Lyophilized powder: Store at or below 8 °C, sealed and protected from heat, light, and moisture.

MOTS-c vs. 5-Amino-1MQ vs. Humanin Comparison

MOTS‑c Safety & Side Effects

In animal studies, MOTS‑c demonstrated an impressively favorable safety profile, with no signs of toxicity even during long‑term administration. Mice treated with MOTS‑c showed improved metabolic parameters, such as insulin sensitivity, mitochondrial resilience, and physical endurance, without evidence of organ damage or adverse reactions.

In humans, clinical data are sparse but encouraging. A 2021 pilot trial in older adults (“Reynolds et al.”) suggested no serious adverse events, with participants tolerating MOTS‑c well while experiencing metabolic benefits .

Additionally, exercise (a natural inducer of MOTS‑c) has been shown to raise circulating MOTS‑c levels without any reported side effects.

There have been no reported serious side effects in either preclinical or clinical settings.

Given its role in promoting metabolism, cell survival, and mitochondrial-nuclear signaling via AMPK activation, theoretical concerns have been raised about potential interactions with AMPK-activating medications or cancer biology, though no direct evidence links MOTS‑c to carcinogenesis.

Important: Regulatory bodies have not approved MOTS‑c for human use. It remains strictly research-use-only, and its long-term safety in humans is not yet established.

Legal Disclaimer

MOTC-s is intended for laboratory research purposes only. It is not approved for human or veterinary use, and must not be used for diagnostic, therapeutic, or resale applications.

By purchasing this product, you agree to use it in compliance with all applicable laws and regulations.

MOTC-s Certificate of Analysis (COA)

All Evolve Peptides products, including MOTS-c, undergo rigorous third-party testing to verify identity, purity, and quality. Each batch is accompanied by a Certificate of Analysis (COA) generated by an independent laboratory, ensuring researchers have full transparency into the peptide’s composition and integrity. COAs are available upon request and may be downloadable directly from select product pages.

To further support research integrity, we welcome third-party verification from our customers—if your own lab results show discrepancies, we’ll replace the product at no cost. This commitment to quality and accountability sets Evolve apart as a trusted source for research-grade peptides.

Scientific References

1. Lu, C., Zeng, J., Drew, B. G., Sallam, T., Martin-Montalvo, A., Wan, J., … Cohen, P. (2015). The mitochondrial-derived peptide MOTS‑c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism, 21(3), 443–454. https://www.cell.com/cell-metabolism/fulltext/S1550-4131(15)00061-3

[PMCID PMC4350682]

1. Yoon, T. K., Lee, C. H., Kwon, O., & Kim, M. S. (2022). Exercise, mitohormesis, and mitochondrial ORF of the 12S rRNA type-C (MOTS‑c). Diabetes & Metabolism Journal, 46(3), 402–413. https://e-dmj.org/journal/view.php?doi=10.4093/dmj.2022.0092
2. Wan, W., Zhang, L., Lin, Y., Rao, X., Wang, X., Hua, F., & Ying, J. (2023). Mitochondria-derived peptide MOTS‑c: Effects and mechanisms related to stress, metabolism and aging. Journal of Translational Medicine, 21(1), 36. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-03885-2
3. Mohtashami, Z., Singh, M. K., Salimiaghdam, N., Ozgul, M., & Kenney, M. C. (2022). MOTS‑c, the most recent mitochondrial‑derived peptide in human aging and age‑related diseases. International Journal of Molecular Sciences, 23(19), 11991. https://www.mdpi.com/1422-0067/23/19/11991
4. 5. Zheng Y, Wei Z, Wang T. (2023). MOTS‑c: A promising mitochondrial‑derived peptide for therapeutic exploitation [Review]. Metabolism & Aging*, Front Endocrinol (Lausanne). 2023 Jan 25:14:1120533. https://pubmed.ncbi.nlm.nih.gov/36761202/ PMCID PMC9905433
5. Lu, H., Fan, L., Zhang, W., Chen, G., Xiang, A., Wang, L., Lu, Z., & Zhai, Y. (2024). The mitochondrial genome‑encoded peptide MOTS‑c interacts with Bcl‑2 to alleviate nonalcoholic steatohepatitis progression. Cell Reports, 43(1), 113587. https://linkinghub.elsevier.com/retrieve/pii/S2211124723015991
6. Yerra, V. G., & Connelly, K. A. (2025). MOTS‑c: Magical molecule for diabetic cardiomyopathy? Cardiovascular Drugs and Therapy, 39(3), 473–476.  https://link.springer.com/article/10.1007/s10557-025-07689-y
7. Lu, H., Wei, M., Zhai, Y., Li, Q., Ye, Z., Wang, L., Luo, W., Chen, J., & Lu, Z. (2019). MOTS‑c peptide regulates adipose homeostasis to prevent ovariectomy‑induced metabolic dysfunction. Journal of Molecular Medicine, 97(4), 473–485.
   https://link.springer.com/article/10.1007/s00109-018-01738-w