MOTS-c
MOTS-c Description MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c) is a mitochondria-derived peptide discovered in 2015 that functions as a mitochondrial-encoded regula tory signal. The 16-amino acid peptide is encoded by the mitochondrial genome within the 12S rRNA gene and represents an important link between mitochondrial function and metabolism. MOTS-c primarily targets skeletal muscle and acts as a metabolic regulator by activating the AMPK (AMP-activated protein kinase) pathway, which is crucial for cellular energy homeostasis. Peptide Information Property Value Peptide Sequence Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg Molecular Formula C101H152N28O22S2 Molecular Weight 2174.6 g/mol CAS Number 1627580-64-6 PubChem CID 255386757 Synonyms 1627580-64-6, UNII-A5CV6JFB78, MOTS-c (human) (trifluoroacetate salt), A5CV6JFB78 MOTS-c Research What is the research background of MOTS-c? Mitochondria, serving as the “powerhouse” of cells, play a crucial role in maintaining cellular homeostasis. The communication mechanisms between mitochondria and the nucleus have long been a focus of scientific research. Mitochondria possess an independent genome. Beyond the classic 37 genes, recent studies have revealed that mitochondrial DNA also encodes biologically active short peptides, one of which is the mitochondrial-derived peptide MOTS-c, encoded by the mitochondrial 12S rRNA region. This discovery significantly expands the scope of mitochondrial genetics, offering a novel perspective for elucidating crucial biological processes such as mitochondrial-nuclear communication and metabolic regulation. Currently, treatments for numerous challenging diseases like diabetes and chronic hepatitis B face significant bottlenecks. MOTS-c's prominent role in skeletal muscle metabolic regulation, such as enhancing glucose metabolism, suggests its potential in treating metabolic disorders. Furthermore, abnormal MOTS-c levels observed in various disease processes have prompted researchers to investigate its role in disease onset, progression, and treatment, seeking new avenues to overcome these intractable conditions. What is the mechanism of action for MOTS-c? Regulating Metabolism-Related Signaling Pathways Activating the AICAR-AMPK Signaling Pathway: MOTS-c activates the AICAR-AMPK signaling pathway by disrupting the intracellular folate-methionine cycle. Activated AMPK regulates cellular energy metabolism, such as promoting glucose uptake and fatty acid oxidation. In glucose metabolism, it increases the translocation of the glucose transporter GLUT4 to the cell membrane, thereby enhancing cellular glucose uptake capacity, improving insulin resistance, and aiding in the prevention and treatment of metabolic diseases like type 2 diabetes[1]. Effects on Other Pathways: Beyond the AMPK pathway, MOTS-c also acts on the AKT pathway, oxidative stress pathway, and inflammation-related pathways. Regarding the AKT pathway, it may influence cellular processes like growth, proliferation, and survival by regulating the pathway's activity. In the oxidative stress pathway, MOTS-C reduces intracellular oxidative stress levels, decreases reactive oxygen species (ROS) production, and protects cells from oxidative damage. In inflammation-related pathways, it suppresses the release of inflammatory mediators and alleviates inflammatory responses. For instance, in inflammatory pain models, MOTS-C reduces inflammatory mediator release in the dorsal horn of the spinal cord, thereby improving pain symptoms[2]. Figure 1 The primary physiological functions of MOTS-C include reducing insulin resistance, preventing obesity, improving muscle function, promoting bone metabolism, enhancing immune regulation, and delaying aging[1]. Regulation of Gene Expression Nuclear Gene Expression Regulation: When cells encounter metabolic stress, such as glucose restriction and oxidative stress, MOTS-C translocates to the nucleus to directly regulate adaptive nuclear gene expression, thereby promoting intracellular homeostasis. For example, MOTS-C modulates the expression of metabolism-related genes like GLUT4, STAT3, and IL-10, influencing physiological processes including glucose metabolism and immune regulation. Increased GLUT4 expression enhances cellular glucose uptake; STAT3 participates in cell proliferation, differentiation, and immune regulation; IL-10, an anti-inflammatory cytokine, reduces inflammatory responses when its expression is elevated[1,3]. Enhancing Energy Metabolism Enhanced Glycolysis: In various disease models, such as the lung ischemia-reperfusion injury (LIRI) model induced by cardiopulmonary bypass (CPB), MOTS-c pretreatment enhances glycolytic flux in pulmonary microvascular endothelial cells (PMVECs). It mitigates LIRI injury by restoring cellular energy homeostasis and reducing lipid peroxidation through upregulating the key glycolytic enzyme PFKFB3. This demonstrates that MOTS-c modulates the glycolytic pathway to supply sufficient energy for cells under stress, thereby maintaining normal cellular function[4]. Cellular Protection Effects Mitigation of Mitochondrial Damage: In a radiation pneumonitis (RP) model, MOTS-c significantly reduced lung tissue injury, inflammation, and oxidative stress while reversing alveolar epithelial cell apoptosis and mitochondrial damage. This mechanism involves increasing nuclear factor E2-related factor 2 (Nrf2) levels and promoting its nuclear translocation. Nrf2 activates a series of antioxidant and cell-protective genes, safeguarding mitochondrial function. This demonstrates that MOTS-c protects damaged tissues by preserving mitochondria and reducing apoptosis[5]. Protection of Other Cells: In studies on Duchenne muscular dystrophy (DMD), MOTS-c was found to possess intrinsic muscle-targeting properties. It enhances glycolytic flux and energy production capacity in dystrophic muscles, contributing to improved muscle function. Furthermore, in inflammatory pain models, MOTS-c administered centrally or peripherally alleviates pain hypersensitivity by suppressing inflammatory responses and neuronal hyperexcitability, offering neuroprotective effects[2,6]. What are the applications of MOTS-c? Treatment of Metabolic Disorders: Improving insulin resistance and preventing diabetes: MOTS-c enhances insulin resistance, which is crucial for preventing type 2 diabetes. Insulin resistance is a key factor in the onset of type 2 diabetes. MOTS-c may improve insulin sensitivity by activating the AICAR-AMPK signaling pathway and regulating the intracellular folate-methionine cycle. Research by Gao Y indicates it promotes skeletal muscle glucose uptake and utilization, akin to opening additional glucose absorption pathways in cells, thereby lowering blood glucose levels[1]. Regulating lipid metabolism and combating obesity: Regarding lipid metabolism, MOTS-c increases brown fat thermogenesis and promotes white fat browning. Brown fat consumes energy through thermogenesis, while white fat browning signifies the transformation of energy-storing white fat into energy-consuming brown fat. This process aids the body in adapting to cold and, more importantly, prevents obesity and lipid metabolism disorders, offering new insights for obesity prevention and treatment [1]. Prevention and Treatment of Muscle-Related Diseases: Promoting Muscle Differentiation: In vitro studies show that wild-type MOTS-c peptide enhances myotubular formation in human (LHCN-M2) and mouse (C2C12) muscle progenitor cells, whereas the Y8F mutant peptide lacks this effect. Further studies revealed that MOTS-c enhances myotubulogenesis by interacting with the IL-6/Janus kinase/signal transducer and activator of transcription 3 (STAT3) pathway, thereby reducing STAT3 transcriptional activity[7]. Prevention of Muscle Atrophy: Plasma MOTS-c levels negatively correlate with myostatin levels. MOTS-c prevents palmitate-induced myotube atrophy in differentiated C2C12 cells and reduces plasma myostatin levels in diet-induced obese mice. It prevents muscle atrophy by enhancing AKT phosphorylation, inhibiting the activity of FOXO1—an upstream transcription factor of myostatin and other muscle-atrophy genes—while regulating mTORC2 and PTEN activity and increasing CK2 activity to suppress PTEN[8]. Anti-aging effects: MOTS-c expression changes are closely linked to aging, and it exhibits anti-aging properties. This is achieved through multiple mechanisms, including improving glucose and lipid metabolism, enhancing cellular mitochondrial function, and reducing systemic chronic inflammation. Research by Gao Y et al. indicates that improved metabolism provides cells with more abundant and stable energy supply. Enhancing mitochondrial function is akin to upgrading the cell's “energy factory,” while reducing inflammatory responses minimizes inflammatory damage to cells[1]. Conclusion As a mitochondrial-derived peptide, MOTS-c activates signaling pathways like AMPK to regulate glucose and lipid metabolism, promote white-to-brown fat conversion, and improve insulin resistance and obesity, offering novel therapeutic directions for metabolic disorders. It enhances osteoblast differentiation, suppresses osteoclast formation, balances bone metabolism, and supports skeletal health maintenance. It regulates muscle differentiation and prevents atrophy, holding potential for intervention in muscle-related disorders. MOTS-c exhibits strong exercise-related associations: exercise upregulates its expression, and it mediates exercise-induced health benefits. MOTS-c also plays a role in delaying aging and related processes. Relevant Citations [1] Gao Y, Wei X, Wei P, et al. MOTS-c Functionally Prevents Metabolic Disorders. Metabolites 2023; 13(1).DOI: 10.3390/metabo13010125. [2] Wang Z, Yang L, Xu L, Liao J, Lu P, Jiang J. Central and peripheral mechanism of MOTS-c attenuates pain hypersensitivity in a mice model of inflammatory pain. Neurological Research 2024; 46(2): 165-177.DOI: 10.1080/01616412.2023.2258584. [3] Benayoun BA, Lee C. MOTS-c: A Mitochondrial-Encoded Regulator of the Nucleus. Bioessays 2019; 41(9): e1900046.DOI: 10.1002/bies.201900046. [4] Shen Z, Lu P, Jin W, et al. MOTS-c Promotes Glycolysis via AMPK-HIF-1α-PFKFB3 Pathway to Ameliorate CPB-induced Lung Injury. American Journal of Respiratory Cell and Molecular Biology 2025. 10.1165/rcmb.2024-0533OC. [5] Zhang Y, Huang J, Zhang Y, et al. The Mitochondrial-Derived Peptide MOTS-c Alleviates Radiation Pneumonitis via an Nrf2-Dependent Mechanism. Antioxidants 2024; 13. https://api.semanticscholar.org/CorpusID:269876125. [6] Ran N, Lin C, Leng L, et al. MOTS-c promotes phosphorodiamidate morpholino oligomer uptake and efficacy in dystrophic mice. Embo Molecular Medicine 2021; 13(2): e12993.DOI: 10.15252/emmm.202012993. [7] García-Benlloch S, Revert-Ros F, Blesa JR, Alis R. MOTS-c promotes muscle differentiation in vitro. Peptides 2022; 155: 170840.DOI: 10.1016/j.peptides.2022.170840. [8] Kumagai H, Coelho AR, Wan J, et al. MOTS-c reduces myostatin and muscle atrophy signaling. American Journal of Physiology-Endocrinology and Metabolism 2021; 320(4): E680-E690.DOI: 10.1152/ajpendo.00275.2020. For Research Use OnlyThis compound is provided exclusively for in vitro laboratory research. It is not intended for human or animal consumption, diagnosis, treatment, or medical use. Not for dietary, cosmetic, or veterinary purposes. This product has not been evaluated by the U.S. Food and Drug Administration or any other regulatory authority. DisclaimerAll information is for educational purposes only. Humatide makes no claims regarding efficacy or safety. Purchasers are responsible for ensuring proper handling and use in compliance with all applicable laws and regulations. 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