MOTS-c (10mg)

The compound was first characterized in 2015, where it was reported to act on the folate–methionine cycle and downstream one-carbon metabolism, with accumulation of the purine intermediate AICAR and subsequent AMPK activation observed in cell and rodent models [1]. That AMPK-linked mechanism has anchored most subsequent laboratory work.

A 2018 study reported that MOTS-c translocates from the cytosol to the nucleus under metabolic stress and interacts with stress-responsive transcription factors including NFE2L2/NRF2 at antioxidant response elements [2]. This is the basis for describing the molecule as a mitochondrial-to-nuclear signal rather than a purely cytosolic one. Work on glucose transporter handling has been examined alongside it, with one study reporting that OPA1 and MFN2 mediated mitochondrial fusion was required for MOTS-c associated GLUT4 translocation in cultured mammalian cell and adipocyte models [3]. Researchers comparing mitochondrial-targeted compounds may find the SS-31 and MOTS-c comparison guide useful context, as is the overview of how NAD+ differs structurally from peptides.

The research threads below cover the two areas where published data is most developed.

Kinase Binding and Skeletal Muscle Signaling

A 2024 cell-free binding study reported that MOTS-c binds directly to protein kinase CK2 and activates it, with tissue-differential activity observed between skeletal muscle and adipose tissue [4]. An earlier report described a CK2 to PTEN to mTORC2 to AKT to FOXO1 cascade associated with reduced myostatin expression in C2C12 myotubes exposed to palmitic acid [5].

Myogenic Differentiation Models

In vitro work in LHCN-M2 and C2C12 myoblast lines reported increased myotube formation following exposure to wild-type MOTS-c, an outcome not observed with the Y8F mutant variant, which points to a defined sequence region as the active site [6].

Exercise-responsive expression has also been examined in study populations and rodent models, where circulating levels were reported to change with physical activity and with age [7]. Broader reviews place MOTS-c within the wider mitochondrial-derived peptide family studied in aging research models [8].

References

1. Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P. (2015). The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance. Cell Metabolism, 21(3), 443–454. https://doi.org/10.1016/j.cmet.2015.02.009
2. Kim KH, Son JM, Benayoun BA, Lee C. (2018). The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell Metabolism, 28(3), 516–524.e7. https://doi.org/10.1016/j.cmet.2018.06.008
3. Bhullar KS, Shang N, Kerek E, Wu K, Wu J. (2021). Mitofusion is required for MOTS-c induced GLUT4 translocation. Scientific Reports, 11, 14291. https://doi.org/10.1038/s41598-021-93735-2
4. Kumagai H, Kim SJ, Miller B, Zempo H, Tanisawa K, Natsume T, et al. (2024). MOTS-c modulates skeletal muscle function by directly binding and activating CK2. iScience, 27(11), 111212. https://doi.org/10.1016/j.isci.2024.111212
5. Kumagai H, Coelho AR, Wan J, Mehta HH, Yen K, Huang A, Zempo H, Fuku N, Maeda S, Oliveira PJ, Cohen P, Kim SJ. (2021). MOTS-c reduces myostatin and muscle atrophy signaling. American Journal of Physiology-Endocrinology and Metabolism, 320(4), E680–E690. https://doi.org/10.1152/ajpendo.00275.2020
6. García-Benlloch S, Revert-Ros F, Blesa JR, Alis R. (2022). MOTS-c promotes muscle differentiation in vitro. Peptides, 155, 170840. https://doi.org/10.1016/j.peptides.2022.170840
7. Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, Lu R, Cohen P, Graham NA, Benayoun BA, Merry TL, Lee C. (2021). MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications, 12, 470. https://doi.org/10.1038/s41467-020-20790-0
8. Mohtashami Z, Singh MK, Salimiaghdam N, Ozgul M, Kenney MC. (2022). MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases. International Journal of Molecular Sciences, 23(19), 11991. https://doi.org/10.3390/ijms231911991