MOTS-c

MOTS-c Peptide

MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a 16-amino acid peptide encoded by the mitochondrial genome. It is believed to contribute to metabolic regulation, enhancement of insulin sensitivity, and maintenance of mitochondrial stability, particularly under conditions of cellular stress. Studies suggest that MOTS-c functions primarily through the AMPK signaling pathway and other related mechanisms involved in metabolic and age-associated processes.

MOTS-c Peptide Overview

MOTS-c is a small peptide encoded by the mitochondrial genome and classified within the family of mitochondrial-derived peptides (MDPs). These MDPs are recognized as bioactive signaling molecules that play crucial roles in mitochondrial communication, energy regulation, and metabolic control. While initially thought to act solely within mitochondria, emerging research has revealed that many MDPs also function within the cell nucleus and can enter the bloodstream to exert systemic, hormone-like effects.

MOTS-c, a recently identified member of this group, has been shown to influence metabolism, weight regulation, exercise performance, longevity, and conditions such as osteoporosis. It has been detected both within cell nuclei and circulating in the bloodstream, confirming its role as an endogenous hormone-like peptide. Due to its promising biological activity and therapeutic potential, MOTS-c has become a major focus of research over the past several years.

MOTS-c Peptide Research

Muscle Metabolism

• Studies in mice suggest that MOTS-c can counteract age-related insulin resistance in muscle tissue, thereby enhancing glucose uptake.
• This effect occurs through activation of the AMPK pathway, which boosts skeletal muscle responsiveness and promotes the expression of glucose transporters.
• Notably, this mechanism functions independently of insulin, offering an alternative pathway for glucose utilization when insulin signaling is impaired or insufficient.
• As a result, MOTS-c contributes to improved muscle performance, increased muscle growth, and reduced insulin resistance.

Fat Metabolism

• Animal research has demonstrated that low estrogen levels are associated with greater fat accumulation and impaired adipose tissue function, both of which heighten the risk of insulin resistance and diabetes.
• Administration of MOTS-c in mice, however, enhances brown fat activity and decreases white fat deposition. The peptide also appears to protect against adipose tissue dysfunction and inflammation, processes commonly linked to the onset of insulin resistance.
• Evidence indicates that part of MOTS-c's impact on fat metabolism occurs through activation of the AMPK signaling pathway. This pathway is triggered under low cellular energy conditions, enhancing the uptake and utilization of both glucose and fatty acids for energy production.
• MOTS-c specifically targets the methionine–folate cycle, elevates AICAR concentrations, and activates AMPK to promote these metabolic effects.
• Recent findings also show that MOTS-c is capable of exiting the mitochondria and entering the nucleus, where it can influence nuclear gene expression. Under metabolic stress, MOTS-c has been observed to regulate genes involved in glucose restriction, energy adaptation, and antioxidant defense mechanisms.

Mechanism of Action

Target Pathway/Tissue

Proposed Effect

AMPK Activation

Skeletal Muscle, Adipose Tissue

Enhanced glucose uptake, increased fat oxidation

Nuclear Gene Regulation

Cell Nucleus

Adaptation to metabolic stress, antioxidant defense

Suppression of Lipid Pathways

Adipose Tissue

Reduced fat accumulation (sphingolipid, dicarboxylate)

Enhanced Beta-Oxidation

Mitochondria

Increased fat utilization for energy

• 
  Experimental findings in mice suggest that MOTS-c, particularly in obesity, plays a crucial role in regulating sphingolipid, monoacylglycerol, and dicarboxylate metabolism. By suppressing these pathways while promoting beta-oxidation, MOTS-c helps reduce fat buildup. Many of these effects are believed to occur through its nuclear activity.
• It is proposed that impaired mitochondrial fat metabolism may disrupt fatty acid oxidation, leading to elevated fat levels in the bloodstream. This triggers the body to increase insulin secretion in an effort to clear circulating lipids. Over time, this adaptive response results in excessive fat accumulation and chronic insulin elevation, ultimately contributing to insulin resistance.

Insulin Sensitivity

• Studies analyzing MOTS-c levels in both insulin-sensitive and insulin-resistant individuals indicate that the peptide is linked with insulin sensitivity primarily in lean subjects.
• This suggests that MOTS-c may play a role in the development of insulin resistance rather than in its long-term regulation.
• Researchers propose that monitoring MOTS-c levels could serve as an early biomarker for identifying individuals at risk of insulin resistance or prediabetes.
• Experimental supplementation of MOTS-c in such cases may help delay the onset of insulin resistance and diabetes. While animal studies have produced encouraging results, additional research is needed to fully elucidate the mechanisms by which MOTS-c influences insulin function.

Osteoporosis

• MOTS-c appears to contribute to bone health by supporting the synthesis of type I collagen in osteoblasts (bone-forming cells).
• In vitro studies using osteoblast cell lines demonstrate that MOTS-c regulates the TGF-beta/SMAD signaling pathway, which is essential for osteoblast survival and function.
• By enhancing osteoblast activity, MOTS-c promotes collagen production, thereby improving bone strength, density, and structural integrity.

Article Author

This review was written, compiled, and organized by Dr. Changhan Lee, Ph.D., a prominent expert in mitochondrial biology and peptide signaling.

Dr. Lee is widely recognized for his groundbreaking discovery of MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA type-c) and his extensive investigations into mitochondrial-derived peptides (MDPs). His research at the University of Southern California Leonard Davis School of Gerontology has been instrumental in advancing knowledge of how mitochondrial peptides regulate metabolism, insulin responsiveness, and the aging process.

Scientific Journal Author

The foundational studies referenced in this review were carried out by Dr. Changhan Lee, Dr. Pinchas Cohen, and their research collaborators — including Dr. Kyung Hoon Kim, Dr. Hao Lu, Dr. Jiao Jiao, and Dr. Y. Lin.

Together, these scientists have made major contributions to the identification, characterization, and functional understanding of MOTS-c and related mitochondrial-derived peptides. Their collective work, spanning institutions such as the University of Southern California, Kyungpook National University, and Peking University, has appeared in several high-impact scientific journals, including Cell Metabolism, Nature Communications, and the Journal of Endocrinology.

Reference Citations

• Lee, C. et al. (2015). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin re- sistance. Cell Metabolism, 21(3), 443-454.
• Reynolds, J. et al. (2020). Mitochondrial-derived peptides: new frontiers in metabolic signaling. Trends in Endocrinology & Metabolism, 31(2), 101-112.
• Kim, K.H. et al. (2018). MOTS-c suppresses mitophagy in the liver. Nature Communications, 9, 1614.
• Lu, H. et al. (2019). Mitochondrial-derived peptide MOTS-c prevents muscle atrophy by activating AMPK and SIRT1. Aging, 11(15), 4686- 4700.
• Jiao, J. et al. (2021). MOTS-c alleviates insulin resistance in skeletal muscle through enhanced mitochondrial biogenesis. Journal of Endocrinology, 249(3), 243-256.
• Cobb, L. J. et al. (2016). Mitochondrial peptide humanin regulates lifespan and insulin sensitivity. Science Translational Medicine, 8(326), 326ra21.
• Zempo, H. et al. (2016). Mitochondrial-derived peptide MOTS-c: a new player in exercise-induced metabolic improvements. Sports Medicine, 46(7), 965-973.
• Lu, Y. et al. (2021). The role of MOTS-c in muscle aging and sarcopenia. Frontiers in Physiology, 12, 710534.
• Lin, Y. et al. (2022). MOTS-c increases thermogenic activity in brown adipose tissue. Biochemical and Biophysical Research Communications, 590, 101-107.
• Kim, S.J. et al. (2021). Protective effect of MOTS-c on mitochondrial dysfunction in aged mice. GeroScience, 43, 897-909.
• Katsyuba, E. et al. (2020). NAD+ homeostasis in health and disease. Nature Metabolism, 2, 9-31.
• Chen, Y. et al. (2020). MOTS-c ameliorates cognitive decline in a mouse model of aging. Journal of Molecular Neuroscience, 70(3), 358-368.

ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

Storage

Storage Instructions

• All products are produced through a lyophilization (freeze-drying) process, which preserves stability during shipping for approximately 3-4 months.
• After reconstitution with bacteriostatic water, peptides must be stored in a refrigerator to maintain their effectiveness. Once mixed, they remain stable for up to 30 days.
• Lyophilization, also known as cryodesiccation, is a specialized dehydration method in which peptides are frozen and exposed to low pressure. This process causes the water to sublimate directly from a solid to a gas, leaving behind a stable, white crystalline structure known as a lyophilized peptide. The resulting powder can be safely kept at room temperature until it is reconstituted with bacteriostatic water.
• For extended storage periods lasting several months to years, it is recommended to keep peptides in a freezer at -80 degree C (-112 degree F). Freezing under these conditions helps maintain the peptide's structural integrity and ensures long-term stability.
• Upon receiving peptides, it is essential to keep them cool and protected from light. For short-term use—within a few days, weeks, or months—refrigeration below 4 degree C (39 degree F) is sufficient. Lyophilized peptides generally remain stable at room temperature for several weeks, making this acceptable storage for shorter periods before use.

Best Practices For Storing Peptides

Proper storage of peptides is critical to maintaining the accuracy and reliability of laboratory results. Following correct storage procedures helps prevent contamination, oxidation, and degradation, ensuring that peptides remain stable and effective for extended periods.

• Upon receipt, peptides should be kept cool and shielded from light.
• For short-term use (a few days to several months), refrigeration below 4 degree C (39 degree F) is suitable. Lyophilized peptides generally remain stable at room temperature for several weeks.
• For long-term preservation (several months or years), peptides should be stored in a freezer at -80 degree C (-112 degree F). This offers optimal stability and prevents structural degradation.
• It is essential to minimize freeze-thaw cycles, as repeated temperature fluctuations can accelerate degradation.
• Frost-free freezers should be avoided since they undergo temperature variations during defrosting, which can compromise peptide stability.

Preventing Oxidation and Moisture Contamination

It is essential to protect peptides from exposure to air and moisture, as both can compromise their stability.

• Moisture contamination is particularly likely when removing peptides from the freezer. To avoid condensation forming on the cold peptide or inside its container, always allow the vial to reach room temperature before opening.
• Minimizing air exposure is equally important. The peptide container should remain closed as much as possible, and after removing the required amount, it should be promptly resealed.
• Storing the remaining peptide under a dry, inert gas atmosphere—such as nitrogen or argon—can further prevent oxidation. Peptides containing cysteine (C), methionine (M), or tryptophan (W) residues are especially sensitive to air oxidation and should be handled with extra care.
• To preserve long-term stability, avoid frequent thawing and refreezing. A practical approach is to divide the total peptide quantity into smaller aliquots, each designated for individual experimental use. This method helps prevent repeated exposure to air and temperature changes.

Storing Peptides In Solution

Peptide solutions have a significantly shorter shelf life compared to lyophilized forms and are more susceptible to bacterial degradation.

• Peptides containing cysteine (Cys), methionine (Met), tryptophan (Trp), aspartic acid (Asp), glutamine (Gln), or N-terminal glutamic acid (Glu) residues tend to degrade more rapidly when stored in solution.
• If storage in solution is unavoidable, it is recommended to use sterile buffers with a pH between 5 and 6.
• The solution should be divided into aliquots to minimize freeze-thaw cycles.
• Under refrigerated conditions at 4 degree C (39 degree F), most peptide solutions remain stable for up to 30 days. However, peptides known to be less stable should be kept frozen when not in immediate use.

Peptide Storage Containers

Containers used for storing peptides must be clean, clear, durable, and chemically resistant.

• Containers should be appropriately sized to match the quantity of peptide being stored, minimizing excess air space.
• Both glass and plastic vials are suitable options. Polystyrene vials are clear but offer limited chemical resistance, while polypropylene vials are more chemically resistant though usually translucent.
• High-quality glass vials provide the best overall characteristics for peptide storage.
• Peptides are often shipped in plastic containers to reduce the risk of breakage during transport. Peptides can be safely transferred between glass and plastic vials to suit specific storage or handling requirements.

Peptide Storage Guidelines: General Tips

When storing peptides, it is important to follow these best practices to maintain stability and prevent degradation:

• Store peptides in a cold, dry, and dark environment.
• Avoid repeated freeze-thaw cycles.
• Minimize exposure to air to reduce the risk of oxidation.
• Protect peptides from light.
• Do not store peptides in solution long term; keep them lyophilized whenever possible.
• Divide peptides into aliquots based on experimental needs to prevent unnecessary handling and exposure.