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▎What is MOTS-c?
MOTS-c is a mitochondrial-derived peptide encoded by the 12S rRNA region of mitochondrial DNA, consisting of 16 amino acids. As a mitochondrial retrograde signal, MOTS-c can translocate to the cell nucleus under conditions such as metabolic stress, regulating the expression of a series of genes associated with metabolic dysfunction. It is widely distributed in various organ tissues such as the kidneys, heart muscle, and skeletal muscle, and is also present in plasma. It can cross the blood-brain barrier and regulate cellular energy balance, glucose, and lipid metabolism by activating the AMPK pathway, playing a crucial role in maintaining metabolic health. It has effects in improving insulin resistance, preventing type 2 diabetes, regulating fat metabolism, and protecting cardiovascular and neural health.
▎MOTS-c Structure
Source: PubChem | Sequence: MRWQEMGYIFYPRKLR Molecular Formula: C101H152N28O22S2 Molecular Weight: 2174.6g/mol CAS Number: 1627580-64-6 PubChem CID: 146675088 Synonyms: UNII-A5CV6JFB78 |
▎MOTS-c Research
What is the research background of MOTS-c?
The research background of MOTS-c originated from investigations into the role of mitochondrial DNA in metabolic health and aging. As understanding of mitochondrial function deepened, it was discovered that mitochondria are not only the center of energy metabolism but also participate in cellular communication and signal transduction. By activating the AMPK pathway, they are involved in glucose and lipid metabolism, closely related to metabolic diseases such as diabetes and obesity, and hold promise as new therapeutic targets for these conditions. Given the association between mitochondrial function and various diseases, MOTS-c has also been applied in conditions such as chronic hepatitis B and ovarian cancer. Research suggests it may play a significant role in viral infection processes. Exercise promotes the synthesis and expression of MOTS-c in the human body, thereby improving muscle metabolism, physical performance, and overall bodily function, providing evidence for exercise-based anti-aging strategies and expanding the scope of MOTS-c research.
What is the mechanism of action of MOTS-c?
Activation of the AICAR-AMPK signaling pathway:
MOTS-c primarily exerts its physiological functions by activating the AICAR-AMPK signaling pathway. It disrupts the folate-methionine cycle within cells, thereby activating the AICAR-AMPK signaling pathway. For example, in physiological processes such as improving insulin resistance and preventing obesity, the activation of this pathway plays a key role. By activating this pathway, MOTS-c can regulate cellular energy metabolism, enhance cellular uptake and utilization of glucose, thereby regulating systemic metabolic homeostasis[1,2].
Interactions with specific signaling pathways and genes:
In muscle cells, MOTS-c interacts with signal transduction and transcription activator 3 (STAT3) through its YIFY domain's putative Src-homologous 2 (SH2) binding motif, reducing STAT3's transcriptional activity and enhancing myotube formation. In radiation pneumonitis, MOTS-c alleviates lung tissue damage, inflammation, and oxidative stress by increasing nuclear factor E2-related factor (Nrf2) levels and promoting its nuclear translocation, thereby protecting mitochondrial function. Additionally, MOTS-c exerts various physiological functions by regulating the expression of genes such as GLUT4, STAT3, and IL-10[3].
Regulation of metabolic pathways:
MOTS-c participates in the regulation of various important metabolic processes, including glucose metabolism, lipid metabolism, and bone metabolism, through autocrine and paracrine mechanisms. In glucose metabolism, it improves insulin resistance and regulates blood glucose levels; in lipid metabolism, it increases brown fat thermogenesis, promotes white fat browning, and prevents obesity and lipid metabolism disorders; in bone metabolism, it promotes osteoblast proliferation, differentiation, and mineralization, inhibits osteoclast generation, and regulates bone metabolism and bone remodeling[4,5].
Figure 1 Mechanism and function of MOTS-c[6].
What are the functions and applications of MOTS-c?
Functions of MOTS-c
Regulatory effects on metabolism:
MOTS-c can improve glucose and lipid metabolism in the body. In glucose metabolism, it reduces insulin resistance, helps prevent type 2 diabetes, and enhances cellular uptake and utilization efficiency of glucose. In lipid metabolism, it increases brown fat thermogenesis, promotes the browning of white fat, thereby regulating lipid metabolism, preventing obesity, and related lipid metabolic disorders. It also reduces the incidence of non-alcoholic fatty liver disease and regulates hepatic lipid metabolism[2].
Effects on cellular function:
It promotes mitochondrial function and protects cells from damage. For example, in radiation-induced pneumonia, it reduces mitochondrial damage in lung epithelial cells, decreases cell apoptosis, and maintains normal cellular function. In pancreatic cells, MOTS-c influences the secretion and expression of insulin and glucagon, regulating pancreatic cell physiology, and also affects cellular viability and apoptosis[4,5].
Effects on muscles and bones:
In muscles, MOTS-c promotes muscle progenitor cell differentiation, increases myotube formation, and protects muscle cells from interleukin-6 (IL-6)-induced damage, potentially preventing muscle atrophy. In terms of bones, it promotes the proliferation, differentiation, and mineralization of osteoblasts, inhibits osteoclast formation, maintains bone metabolic balance, and helps delay osteoporosis[1,5].
Anti-inflammatory and immunomodulatory effects:
MOTS-c reduces systemic chronic inflammatory responses and regulates immune function. In inflammatory pain models, MOTS-c alleviates pain hypersensitivity, reduces the release of inflammatory factors, and inhibits the activation of glial cells and neurons, demonstrating anti-inflammatory and pain-relieving effects [3].
Applications of MOTS-c
Effects on metabolic diseases:
MOTS-c's regulatory effects on glucose and lipid metabolism make it a novel therapeutic target for metabolic diseases such as type 2 diabetes, obesity, and non-alcoholic fatty liver disease[2].
Prevention and Treatment of Musculoskeletal Diseases:
Its positive effects on muscles and bones can be used to prevent and treat muscle atrophy-related diseases and skeletal diseases such as osteoporosis. For patients with muscle atrophy, it can improve muscle function by promoting muscle cell differentiation and inhibiting muscle cell apoptosis; For patients with osteoporosis, it can regulate bone metabolic balance, increase bone density, and prevent and treat osteoporosis [1,5].
Radiation damage protection:
In studies on radiation pneumonitis, MOTS-c has shown protective effects against lung radiation damage. It may be used during radiotherapy to protect normal tissues, reduce radiation-induced tissue damage, and enhance the efficacy of radiotherapy [2].
Treatment of inflammatory diseases:
Based on its anti-inflammatory effects, MOTS-c can be used to treat inflammatory diseases such as inflammatory pain, providing new directions for the treatment of such conditions[3].
Conclusion
As a mitochondrial-derived peptide, MOTS-c can activate signaling pathways to regulate glucose and lipid metabolism, improve insulin resistance, and reduce the risk of metabolic diseases; it can also maintain muscle and bone function, prevent muscle atrophy and osteoporosis; and it possesses anti-inflammatory and cell-protective functions, playing a role in radiation damage protection and the treatment of inflammatory diseases.
About The Author
The above-mentioned materials are all researched, edited and compiled by Cocer Peptides.
Scientific Journal Author
Wan, Yanmin is associated with a variety of prestigious organizations, including hospitals, research centers, universities, and enterprises such as Linping Hosp Integrated Tradit Chinese & Western M, Shanghai Sci Tech Inno Ctr Infect & Immun, Yunnan Agricultural University, etc. His research interests are extensive, primarily focusing on the subject categories of Immunology Science & Technology, Virology, and Materials Science Chemistry. In the field of Immunology Science & Technology, he delves into the mechanisms and applications of the immune system. His Virology research centers on viral characteristics, transmission, and prevention. Within the domain of Materials Science Chemistry, he is committed to the development of material properties and the innovative application of chemistry, making him a notable figure with significant research achievements in relevant academic fields. Wan, Yanmin is listed in the reference of citation [6].
▎Relevant Citations
[1] García-Benlloch S, Revert-Ros F, Blesa J R, et al. MOTS-c promotes muscle differentiation in vitro[J]. Peptides, 2022,155:170840.DOI:10.1016/j.peptides.2022.170840.
[2] Zhang Y, Huang J, Zhang Y, et al. The Mitochondrial-Derived Peptide MOTS-c Alleviates Radiation Pneumonitis via an Nrf2-Dependent Mechanism[J]. Antioxidants, 2024,13.
[3] Wang Z, Yang L, Xu L, et al. Central and peripheral mechanism of MOTS-c attenuates pain hypersensitivity in a mice model of inflammatory pain[J]. Neurological Research, 2024,46(2):165-177.DOI:10.1080/01616412.2023.2258584.
[4] Bień J, Pruszyńska-Oszmałek E, Kołodziejski P, et al. MOTS-c regulates pancreatic alpha and beta cell functions in vitro[J]. Histochemistry and Cell Biology, 2024,161(6):449-460.DOI:10.1007/s00418-024-02274-0.
[5] Yi X, Hu G, Yang Y, et al. Role of MOTS-c in the regulation of bone metabolism[J]. Frontiers in Physiology, 2023,14:1149120.DOI:10.3389/fphys.2023.1149120.
[6] Wan W, Zhang L, Lin Y, et al. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging[J]. Journal of Translational Medicine, 2023,21(1):36.DOI:10.1186/s12967-023-03885-2.
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