Description

MOTS-c

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Peptide Partners Manufacturer Id: WF03

Batch Id: YC20250807

 

Overview

(For educational purposes only)

MOTS-c is a recently discovered mitochondrial-derived peptide that has shown remarkable potential in regulating metabolism, enhancing physical performance, and potentially slowing aspects of aging. This 16-amino acid peptide, encoded by mitochondrial DNA, functions as a crucial signaling molecule between mitochondria and the cell nucleus, with wide-ranging effects on cellular metabolism and stress resistance. Research suggests MOTS-c could have significant therapeutic applications for age-related conditions including diabetes, obesity, and reduced physical capacity.

Origin and Structure of MOTS-c

MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-C) is a 16-amino acid peptide encoded by the 12S rRNA region of the mitochondrial genome^[1][2]. First discovered by Lee and colleagues in 2015, this peptide has a primary structure of Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg, with the first 11 amino acid residues being highly conserved across 14 species, indicating its evolutionary importance^[1][3].

Unlike typical mitochondrial proteins, MOTS-c translation occurs exclusively in the cytoplasm rather than within mitochondria. This is because mitochondrial translation would result in tandem codons using the mitochondria-specific genetic code^[1]. The peptide is widely expressed in numerous tissues, including the brain, heart, liver, skeletal muscle, testes, kidney, spleen, and intestines, suggesting its systemic importance^[3].

Interestingly, MOTS-c is also present in plasma, functioning as a hormone-like signaling molecule, though its circulating levels have been observed to decrease with age—a finding that may have significant implications for age-related diseases^[1][2].

Cellular Mechanism of Action

AICAR-AMPK Pathway Activation

MOTS-c primarily exerts its metabolic effects through the AICAR-AMPK signaling pathway^[3]. This sophisticated mechanism begins with MOTS-c disrupting the folate-methionine cycle in cells, which impedes de novo purine synthesis. This metabolic disruption results in increased levels of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an intermediate metabolite^[3][2].

The accumulated AICAR then activates AMP-activated protein kinase (AMPK), which functions as a master regulator of cellular energy homeostasis^[3][4]. Once activated, AMPK accelerates fatty acid oxidation through the phosphorylation of acetyl-CoA carboxylase (ACC), shifts cellular metabolism toward enhanced glucose uptake, and improves mitochondrial function^[3].

Nuclear Translocation

Under conditions of metabolic stress, MOTS-c dynamically translocates from its typical location near mitochondria to the cell nucleus^[1][5]. This nuclear migration allows MOTS-c to directly influence gene expression, particularly genes involved in stress resistance, protein homeostasis (proteostasis), and metabolic adaptation^[5]. This remarkable ability to shuttle between cellular compartments enables MOTS-c to coordinate the mitochondrial-nuclear communication network essential for maintaining cellular resilience during metabolic challenges^[2].

Physiological Functions and Benefits

Metabolic Regulation

MOTS-c demonstrates powerful effects on whole-body metabolism through several mechanisms:

1.       Enhanced Glucose Metabolism: MOTS-c significantly improves glucose metabolism in skeletal muscle, increasing glucose uptake without stimulating insulin release, effectively functioning as an “exercise mimetic”^[1][4].

2.      Improved Insulin Sensitivity: Treatment with MOTS-c enhances insulin sensitivity, making it potentially valuable for addressing insulin resistance associated with aging and metabolic disorders^[6][3].

3.      Metabolic Flexibility: MOTS-c promotes metabolic flexibility—the ability to efficiently switch between different energy substrates (carbohydrates and fats) based on availability and demand^[5][4]. This adaptability is crucial for maintaining metabolic health throughout aging.

4.      Fat Utilization: Research shows MOTS-c increases the capacity for lipid utilization and fat oxidation, which may contribute to its effects on body composition and weight management^[5][7].

Physical Performance Enhancement

One of the most striking benefits of MOTS-c is its ability to improve physical performance:

1.       Increased Exercise Capacity: Studies in mice demonstrate that MOTS-c treatment significantly improves running endurance and performance across different age groups, from young to old mice^[5].

2.      Enhanced Power Output: MOTS-c-treated mice showed greater power output during exercise compared to control groups, indicating improved muscular efficiency^[5].

3.      Resistance to Fatigue: Treatment enabled higher percentages of mice to reach final running stages (highest speeds) in treadmill tests, suggesting enhanced resistance to fatigue^[5].

4.      Age-Dependent Performance Recovery: Perhaps most remarkably, MOTS-c treatment enabled old mice to outperform untreated middle-aged mice, suggesting not just rejuvenation but a more comprehensive physical reprogramming^[5].

Anti-Aging Properties

MOTS-c demonstrates several mechanisms that may contribute to healthy aging:

1.       NAD+ Elevation: MOTS-c elevates levels of NAD+, a critical metabolic cofactor that declines with age and is associated with longevity in various species^[2].

2.      Methionine Metabolism Restriction: The peptide influences methionine metabolism, a pathway where restriction has been shown to extend lifespan in mice by up to 45%^[2].

3.      Collagen Support: Research shows MOTS-c increases skin collagen by reducing inflammation, potentially slowing skin aging^[2].

4.      Reversal of Age-Related Metabolic Inflexibility: MOTS-c restores metabolic flexibility that typically declines with age, allowing for more efficient adaptation to changing energy demands^[5].

Cellular Protection and Stress Resistance

MOTS-c significantly enhances cellular resilience against various stressors:

1.       Metabolic Stress Protection: In vitro studies show MOTS-c protects cells from glucose restriction and serum deprivation, enhancing survival and recovery^[5].

2.      DNA Repair: Evidence suggests MOTS-c supports DNA repair mechanisms, crucial for limiting age-related cellular damage^[6].

3.      Autophagy Support: MOTS-c may enhance autophagy—the cellular “cleaning” process that removes damaged components—which declines with age^[6].

4.      Heat Shock Response: Gene expression studies reveal MOTS-c regulates heat shock proteins, which help maintain protein folding and stability during stress^[5].

Potential Therapeutic Applications

Based on its diverse physiological effects, MOTS-c shows promise for treating various conditions:

Metabolic Disorders

1.       Type 2 Diabetes: By improving insulin sensitivity and glucose metabolism, MOTS-c may help manage or prevent type 2 diabetes^[1][6][3].

2.      Obesity: Through its effects on metabolic flexibility, fat utilization, and body composition, MOTS-c could assist in weight management approaches^[3][4][7].

Age-Related Conditions

1.       Sarcopenia: The ability of MOTS-c to preserve muscle function could help address age-related muscle loss^[5][2].

2.      Cardiovascular Disease: Metabolic improvements from MOTS-c might reduce cardiovascular risk factors associated with aging^[1][2].

3.      Osteoporosis: Research indicates MOTS-c may promote bone metabolism, potentially benefiting those with osteoporosis^[3][2].

4.      Alzheimer’s Disease: Early evidence suggests potential benefits for neurodegenerative conditions like Alzheimer’s^[2].

Performance Enhancement

While still experimental, MOTS-c’s demonstrated effects on physical performance suggest potential applications for:

1.       Exercise Intolerance: Conditions where physical activity is limited by metabolic factors^[5].

2.      Recovery from Deconditioning: Situations requiring accelerated recovery of physical capacity^[5].

Current Research Evidence

Animal Studies

Multiple studies in mice have demonstrated significant effects of MOTS-c treatment:

1.       Age-Diverse Performance Studies: MOTS-c treatment (15 mg/kg/day) for two weeks improved physical performance in mice of different ages (2, 12, 22, and 23.5 months)^[5][2].

2.      Metabolic Challenge Response: When facing metabolic stress from high-fat diets, MOTS-c-treated mice maintained better running performance and showed reduced fat accumulation^[5].

3.      Metabolic Flexibility Recovery: Old mice treated with MOTS-c recovered circadian metabolic patterns similar to younger mice, indicating restored metabolic flexibility^[5].

4.      Post-Exercise Metabolic Adaptation: Metabolomic analysis showed MOTS-c significantly regulated glycolysis and amino acid metabolism in skeletal muscle after exercise^[5].

Cellular Studies

In vitro research has further illuminated MOTS-c’s cellular mechanisms:

1.       Stress Protection: MOTS-c treatment protected C2C12 myoblast cells from metabolic stress, improving survival approximately 2-fold under glucose restriction and serum deprivation^[5].

2.      Lipid Metabolism: Treatment increased cellular capacity to utilize lipids as fuel sources when glucose was limited^[5].

3.      Gene Expression: RNA sequencing revealed MOTS-c regulation of genes involved in heat shock response, protein folding, and metabolic adaptation^[5].

Conclusion

MOTS-c represents a fascinating example of mitochondrial-nuclear communication with wide-ranging effects on metabolism, physical performance, and cellular resilience. As a mitochondrial-derived peptide that declines with age, MOTS-c supplementation shows promise for addressing multiple aspects of aging and metabolic dysfunction.

Current research suggests MOTS-c functions primarily through AMPK activation, promoting metabolic flexibility, enhancing physical performance, and improving cellular stress resistance. These effects position MOTS-c as a potential therapeutic for conditions including diabetes, obesity, sarcopenia, and other age-related disorders.

While most research remains in preclinical stages, the consistent benefits observed across multiple studies and the peptide’s endogenous nature make MOTS-c a promising candidate for translation to human applications. Future research focusing on optimal dosing, delivery methods, and long-term effects will be crucial to realize the full therapeutic potential of this remarkable mitochondrial-encoded peptide.

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1.       https://pmc.ncbi.nlm.nih.gov/articles/PMC9905433/       

2.      https://pmc.ncbi.nlm.nih.gov/articles/PMC9570330/           

3.      https://pmc.ncbi.nlm.nih.gov/articles/PMC9866798/         

4.      https://www.transformyou.com/mots-c-peptide   

5.       https://www.nature.com/articles/s41467-020-20790-0                    

6.      https://www.renewyouth.com/mots-c-a-potential-anti-aging-peptide/   

7.       https://regenmdwellness.com/products/mots-c