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Mitochondrial-derived peptides (MDPs) have become a major focus in modern metabolic research. Among them, MOTS-C (Mitochondrial Open Reading Frame of the 12S rRNA Type-C) has attracted particular interest for its ability to regulate metabolism, energy balance, and ageing-related processes.
This article explores how mitochondrial peptides like MOTS-C influence metabolic pathways, with an emphasis on its role in energy regulation, insulin sensitivity, and cellular stress response.
MOTS-C is a short peptide encoded by the mitochondrial 12S rRNA gene. Unlike traditional peptides that originate from nuclear DNA, MOTS-C is mitochondrial-derived, making it unique in how it interacts with both mitochondrial and nuclear processes.
In research, MOTS-C functions as a metabolic regulator that helps maintain energy homeostasis and cellular resilience under metabolic stress.
It operates primarily through the Folate–AICAR–AMPK pathway, activating AMP-activated protein kinase (AMPK), a key enzyme that enhances glucose metabolism, fat oxidation, and cellular energy production.
MOTS-C improves mitochondrial efficiency and increases energy expenditure by stimulating AMPK signalling and inhibiting the folate cycle.
Key observed effects include:
In both animal and human studies, MOTS-C treatment has been shown to prevent diet-induced obesity, improve glucose tolerance, and support insulin sensitivity, critical factors for managing metabolic disorders such as obesity and insulin resistance.
Research indicates that MOTS-C is significantly expressed in skeletal muscle, where it plays an essential role in energy regulation and metabolic adaptation.
When exposed to stress or physical activity, MOTS-C translocates from the cytoplasm to the nucleus, where it helps regulate the expression of genes associated with metabolic adaptation and recovery.
These findings position MOTS-C as a key molecular mediator between mitochondrial health, exercise response, and age-related muscle decline.
One of the most widely studied effects of MOTS-C is its ability to improve insulin sensitivity.
MOTS-C enhances glucose metabolism through the AMPK pathway, increasing cellular glucose utilisation and restoring insulin responsiveness in models of metabolic syndrome and type 2 diabetes.
In studies involving mice fed a high-fat diet, MOTS-C treatment prevented obesity, reduced insulin resistance, and maintained healthy blood glucose levels.
This demonstrates MOTS-C’s potential as a metabolic regulator that could one day aid in the management of diabetes and obesity-related disorders.
Emerging research suggests that MOTS-C also plays a role in bone health.
It supports osteoblast proliferation and mineralisation, enhances type I collagen expression, and inhibits osteoclast differentiation, collectively contributing to bone strength and density.
MOTS-C appears to regulate this process through the TGF-β/Smad pathway, offering new insights into its potential in osteoporosis prevention and bone remodelling research.
MOTS-C levels decline with age, which may contribute to reduced metabolic flexibility and physical performance in older individuals.
In studies involving aged mice, MOTS-C treatment improved physical endurance, muscle strength, and overall metabolic health.
It also interacts with NRF2 and other transcription factors to regulate adaptive nuclear gene expression, helping cells respond more effectively to oxidative and metabolic stress.
These findings support the view that MOTS-C could be a potential therapeutic target for age-related metabolic dysfunction and mitochondrial decline.
Cardiovascular studies have revealed that MOTS-C helps reduce oxidative stress, improve endothelial function, and support mitochondrial bioenergetics in cardiac tissues.
Through AMPK activation, MOTS-C improves vascular health and may counteract coronary endothelial dysfunction associated with metabolic diseases.
| Biological Function | Effect of MOTS-C | Pathway/Mechanism |
| Energy metabolism | Increases mitochondrial efficiency | AMPK signalling |
| Insulin sensitivity | Improves glucose uptake and metabolism | AMPK/Folate pathway |
| Fat regulation | Activates brown fat, reduces obesity | Conversion of white to brown adipose tissue |
| Muscle performance | Enhances strength and endurance | Nuclear translocation and adaptive gene expression |
| Bone health | Promotes bone formation and prevents bone loss | TGF-β/Smad pathway |
| Ageing | Improves physical function and stress resistance | NRF2-regulated nuclear response |
To explore related topics in peptide and SARM research, visit:
For researchers investigating mitochondrial peptides, explore our premium-grade MOTS-C.
Developed for scientific and laboratory research, this compound supports the study of metabolic pathways, mitochondrial signalling, and age-related energy regulation.
Each batch undergoes rigorous purity testing to ensure consistency and accuracy in experimental results, a reliable choice for advanced metabolic and longevity research.
MOTS-C is a mitochondrial-derived peptide encoded by the 12S rRNA gene that regulates energy metabolism, glucose uptake, and stress adaptation in cells.
It activates the AMPK pathway, improving glucose metabolism, fat utilisation, and overall energy balance. This makes it important in studies on obesity and insulin resistance.
Yes. MOTS-C enhances mitochondrial function in skeletal muscle, improving endurance, flexibility, and recovery, especially during exercise or metabolic stress.
MOTS-C levels decline with age, but supplementation in research models has been shown to restore metabolic function, support muscle health, and improve physical performance.
MOTS-C promotes bone formation and reduces bone resorption, indicating potential benefits for research into osteoporosis and skeletal ageing.
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