Description
MOTS-c Peptide (Mitochondrial Open Reading Frame of the 12S rRNA-c)
MOTS-c peptide is a novel mitochondria-derived peptide (MDP) consisting of 16 amino acids, identified as a crucial regulator of metabolic homeostasis and cellular adaptation. It is encoded within the mitochondrial DNA and is expressed in various tissues and plasma, acting as both an intracellular signaling molecule and a circulating mitokine. MOTS-c has attracted significant scientific attention for its potential role in modulating metabolism, promoting insulin sensitivity, supporting muscle performance, and influencing age-related cellular processes.
Chemical Information
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Molecular Formula: C₁₀₁H₁₅₂N₂₈O₂₂S₂
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Molecular Weight: 2174.64 g/mol
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Other Names: Mitochondrial-derived peptide MOTS-c, Mitochondrial Open Reading Frame of the 12S rRNA-c
Mechanism of Action
MOTS-c is believed to act primarily through the AMP-activated protein kinase (AMPK) signaling pathway, a key metabolic regulator that maintains energy balance within the cell. Upon metabolic stress, MOTS-c may translocate from the mitochondria to the nucleus, where it can modulate nuclear gene expression, impacting pathways related to metabolism, oxidative stress, and aging.
When expressed or administered experimentally, MOTS-c has been shown to:
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Activate AMPK, promoting glucose uptake, fatty acid oxidation, and mitochondrial biogenesis.
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Enhance insulin sensitivity and support glucose metabolism, particularly in skeletal muscle.
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Influence the folate-methionine cycle and purine biosynthesis, potentially improving energy utilization and reducing metabolic stress.
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Regulate antioxidant response elements (AREs) through transcription factors such as NRF2, supporting the cell’s defense mechanisms against oxidative stress.
Research and Clinical Studies
1. MOTS-c and Muscle Metabolism
Animal and cell studies have suggested that MOTS-c may improve muscle insulin sensitivity by enhancing glucose transporter expression and promoting AMPK activation. This mechanism can potentially lead to greater energy utilization, improved endurance, and enhanced muscle regeneration. MOTS-c has also been observed to influence muscle adaptation in response to metabolic stress and exercise, indicating a role in exercise-induced performance enhancement and age-related muscle maintenance.
In aging models, a decline in endogenous MOTS-c levels has been associated with reduced mitochondrial efficiency and increased metabolic dysfunction, suggesting that MOTS-c may contribute to maintaining metabolic health with age.
2. MOTS-c and Fat Metabolism
MOTS-c has been shown in murine studies to prevent diet-induced obesity by improving insulin sensitivity and promoting lipid oxidation. It appears to inhibit the folate cycle, leading to AMPK activation and enhanced glucose and lipid metabolism. Mice administered MOTS-c displayed lower fat accumulation, greater energy expenditure, and improved glucose tolerance, even under high-fat dietary conditions.
Through these metabolic effects, MOTS-c may represent a novel peptide candidate for studying obesity prevention, insulin resistance, and metabolic syndrome mechanisms.
3. MOTS-c and Bone Health
Research indicates that MOTS-c may play a role in bone tissue regulation through the TGF-β/SMAD signaling pathway. In experimental bone marrow models, MOTS-c increased the expression of genes involved in osteogenic differentiation (such as ALP, Bglap, and Runx2) and promoted bone formation. These effects were attenuated when TGF-β1 was knocked down, suggesting a direct link between MOTS-c activity and bone cell differentiation and remodeling.
This implies potential research applications in understanding osteoporosis, bone density loss, and skeletal tissue regeneration.
4. MOTS-c and Cardiovascular Health
Although MOTS-c may not directly modulate cardiac contractility, research has shown that it might support endothelial function, the inner lining of blood vessels critical for vascular health. By possibly activating AMPK within endothelial cells, MOTS-c could enhance nitric oxide availability and improve vascular reactivity, contributing to healthy blood flow and microvascular integrity.
These findings position MOTS-c as a potential biomarker of endothelial function and a target of interest for studying vascular aging and metabolic-cardiovascular interactions.
5. MOTS-c and Cellular Longevity
Emerging studies suggest that MOTS-c may be linked to cellular longevity and lifespan regulation. Its expression appears to decline with age, and genetic variations affecting MOTS-c production have been correlated with lifespan differences in some populations. By interacting with sirtuins and NAD⁺-dependent pathways, MOTS-c may influence mitochondrial health and delay cellular senescence, making it a subject of research in anti-aging and metabolic resilience studies.
Summary of Potential Research Areas
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Regulation of energy metabolism and cellular adaptation
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Insulin sensitivity and glucose homeostasis mechanisms
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Lipid metabolism and obesity resistance models
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Muscle performance and exercise physiology
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Bone tissue regeneration and osteogenesis
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Endothelial function and vascular health
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Aging, longevity, and mitochondrial communication
References
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Lee C, Kim KH, Cohen P. MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med. 2016;100:182–187. PMCID: PMC5116416
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Mohtashami Z et al. Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases. Int J Mol Sci. 2022;23(19):11991. PMCID: PMC9570330
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Lee C et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443–454. PMCID: PMC4350682
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Lu H et al. MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction. J Mol Med. 2019;97(4):473–485. PMID: 30725119
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Reynolds JC et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12(1):470. PMID: 33473109
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Kim KH et al. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell Metab. 2018;28(3):516–524. PMCID: PMC6185997
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Hu BT, Chen WZ. MOTS-c improves osteoporosis by promoting osteogenic differentiation via TGF-β/Smad pathway. Eur Rev Med Pharmacol Sci. 2018;22(21):7156–7163. PMID: 30468456
Disclaimer: MOTS-c peptide is provided strictly for research and laboratory use only. It is not approved for human consumption, clinical use, or diagnostic purposes. Please review all applicable Terms and Conditions prior to handling or ordering this research compound.
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