What is the use of MOTS-c? And what diseases may be associated with its reduced levels?

MOTS-c is one of the mitochondrial-derived peptides, which has the effects of promoting fatty acid oxidation, promoting white fat browning, enhancing glucose utilization, improving insulin resistance, promoting osteogenesis, inhibiting osteoclasts, etc. It is closely related to obesity, diabetes, non-alcoholic fatty liver disease, metabolic bone disease, etc. Therefore, reduced MOTS-c levels can also be used as a potential diagnostic marker for these diseases.

In diabetes, MOTS-c can improve impaired glucose metabolism caused by aging and high-fat diet. It has been reported that protein kinase CK2 is a functional and direct target of MOTS-c, and reduced binding of K14Q MOTS-c to CK2 increases the risk of type 2 diabetes. In addition, in humans, K14Q MOTS-c carriers have an increased risk of type 2 diabetes, especially in people aged 60 years and above, and daily physical activity can alleviate this increased risk. MOTS-c treatment can also inhibit aging/S961-induced diabetes.

MOTS-c plays a vital role in bone metabolism, helping to stimulate osteoblast proliferation, differentiation and mineralization and inhibit osteoblast apoptosis. In addition, MOTS-c inhibits osteoclast production and mediates the regulation of bone metabolism and bone remodeling. Although exercise can effectively upregulate the expression of MOTS-c, it is unclear whether exercise is a direct effect of regulating the MOTS-c signaling pathway.

MOTS-c can be used as a potential diagnostic biomarker for gestational diabetes mellitus (GDM). The cut-off value of serum MOTS-C level is 173.5 ng/mL, with a sensitivity of 81.8% and a specificity of 61.4% for the diagnosis of GDM. Studies have shown that serum MOTS-C levels in GDM patients are lower than those in healthy pregnant women, fasting blood glucose levels are significantly higher, and increased serum MOTS-C levels are associated with decreased blood glucose levels, supporting the view that mitochondrial dysfunction plays a role in the pathogenesis of GDM.

MOTS-c may be a new potential protective agent against radiation pneumonitis (RP). RP mainly originates from mitochondrial damage to lung epithelial cells. The mitochondrial-derived peptide MOTS-c has been shown to have protective effects against a variety of diseases by alleviating mitochondrial damage. Studies have found that MOTS-c can significantly improve radiation-induced lung tissue damage, inflammation, and oxidative stress. At the same time, MOTS-c reversed apoptosis and mitochondrial damage in alveolar epithelial cells of RP mice. In addition, MOTS-c significantly inhibited oxidative stress and mitochondrial damage in MLE-12 cells and primary mouse lung epithelial cells. This is related to the fact that MOTS-c increases the level of nuclear factor erythroid 2-related factor (Nrf2) and promotes its nuclear translocation. Notably, Nrf2 deficiency abolishes the protective effect of MOTS-c on RP mice. Its mechanism of action is that MOTS-c protects mitochondrial function through an Nrf2-dependent mechanism, thereby alleviating RP.

References:

[1] B. KONG;Young M C;Serin Hong. 1727-P: Mitochondrial-Encoded Peptide MOTS-c Prevents Senescence-Induced Diabetes[J]. ACS Applied Nano Materials, 2023. DOI:10.2337/db23-1727-p.

[2] JIANG F. Mitochondrial-derived peptide MOTS-c and metabolic diseases[C]. 2020. DOI:10.3760/CMA.J.ISSN.1673-4157.2020.01.012.

[3] ZHANG Y, HUANG J, ZHANG Y, et al. The Mitochondrial-Derived Peptide MOTS-c Alleviates Radiation Pneumonitis via an Nrf2-Dependent Mechanism[J]. ACS Applied Nano Materials, 2024. DOI:10.3390/antiox13050613.

[4] ÖZER S, BAYLAN F A, TOK A. Gestational diabetes mellitus is associated with a low serum level of mitochondrial-derived peptide-MOTS-C[J]. Turk biyokimya dergisi = Turkish journal of biochemistry, 2023. DOI:10.1515/tjb-2022-0097.

[5] XUEJIE YI. Role of MOTS-c in the regulation of bone metabolism.[J]. ACS Applied Electronic Materials, 2023. DOI:10.3389/fphys.2023.1149120.

[6] KUMAGAI H, KIM S J, MILLER B, et al. 344-OR: The MOTS-c/CK2 Pathway Is a Novel Molecular Target for Type 2 Diabetes in East Asians[J]. ACS Applied Nano Materials, 2024. DOI:10.2337/db24-344-or.

You may like