Research and Studies in regards to Mots-C

by | Aug 3, 2022 | Research

MOTS-c is a short peptide contained within the mitochondrial genome and is one of a long line of mitochondrial-derived peptides (MDPs). Mitochondrial-derived peptides (MDPs) are peptides found in mitochondrial DNA that help maintain mitochondrial functions and protect cells from stress. According to new research, MDPs play critical roles in mitochondrial communication and energy regulation. MDPs are active in the bloodstream despite being found in the cell nucleus.

MOTS-c peptide, as a member of the MDPs, is vital for exercise capacity, metabolism, longevity, and the potential causes of diseases such as osteoporosis.

Functions Of MOTS-c


The Benefits of MOTS-c in Fat Metabolism

Research suggests that low estrogen levels increase fat mass and adipose tissue dysfunction, thus increasing the likelihood of developing insulin resistance and diabetes. MOTS-c peptide administration may improve brown fat function and decreases fat tissue accumulation in mouse samples. Furthermore, MOTS-c peptide may prevent adipose tissue dysfunction and inflammation after insulin resistance.

MOTS-c peptide influences fat metabolism by activating the AMPK pathway.[1] Yet, the researchers reveal that “MOTS-c activated AMPK pathway to improve energy dissipation and insulin sensitivity.” The AMPK pathway, on the other hand, is a cellular pathway activated when cellular energy levels are low, inducing cells to take up glucose and fatty acids for metabolism. Furthermore, the AMPK pathway is active in ketogenic diets, such as the Atkins diet, which promotes fat metabolism while protecting lean body mass. MOTS-c peptide activates AMPK by targeting the methionine-folate cycle, increasing AICAR levels.

According to research, the peptide can travel from the mitochondria to the nucleus, influencing nuclear gene expression. MOTS-c modulates cellular genes involved in glucose restriction and antioxidant responses during metabolic stress.[2]

MOTS-c peptide is an active modulator of monoacylglycerol, sphingolipid, and dicarboxylate metabolism in obese people. MOTS-c reduces fat accumulation by inhibiting these pathways and increasing beta-oxidation.[3] MOTS-c research into fat deposition and insulin resistance is gaining traction, as scientists believe the peptide may offer a novel approach to addressing the pathophysiology of obesity and diabetes.

Fat oxidation reduces by dysregulation of fat metabolism in the mitochondria. High levels of fat circulation may occur, causing the body to increase insulin levels to combat and clear lipids from the bloodstream. As a result of the body’s response to high insulin levels, there will be increased fat deposition and a homeostatic change. By administering the peptide, these conditions can reverse.


The Benefits of MOTS-c in Muscle Metabolism

MOTS-c peptide functions to reverse age-dependent insulin resistance in muscles, improving glucose uptake. MOTS-c peptide accomplishes this by increasing glucose transporter expression and promoting the response of skeletal muscles to AMPK activation.[4]
It is important to note that activating the AMPK pathway in this context is independent of the insulin pathway, providing another method of increasing glucose uptake of muscles in the event of insulin inactivity or insufficiency. The overall results are as follows:

  • Functional insulin resistance reduces
  • Muscle growth increases
  • Muscle function improves


How MOTS-c May Promote Longevity

MOTS-c research shows that longevity in some human populations requires a change in the peptide, such as the Japanese.[5] The scientists note that “Although more research is needed, we suggest that the m.1382A>C polymorphism located in the MOTS-c encoding mtDNA, which is specific for the Northeast Asian population, may be among the putative biological mechanisms explaining the high longevity of Japanese people.” In this case, a mutation in the MOTS-c peptide gene results in substituting a glutamate residue for lysine, which is in position 14 of the protein. How this change affects the functional aspects of this peptide is unknown, but glutamate has different properties than lysine and can alter the structure and function of the MOTS-c gene.

A substantial amount of research is required to support this thesis, but it is most noticeable in people of the Northeast Asian race and plays an active role in the longevity of this race.


How MOTS-c Impacts Insulin Sensitive Individuals

MOTS-c research in insulin-sensitive and resistant patients reveals that MOTS-c is only associated with insulin sensitivity in lean individuals but does not contribute to maintaining the condition. MOTS-c peptide may be vital in monitoring pre-diabetic thin individuals, according to researchers. They also believe that changes in MOTS-c levels could be a precursor to insulin insensitivity.


MOTS-c and Osteoporosis

MOTS-c plays an active role in Type 1 collagen synthesis, controlled by osteoblasts in the bone. MOTS-c accomplishes this by modulating the TGF-beta/SMAD pathway, which regulates osteoblast health and survival. The ability of the peptide to modulate these pathways promotes osteoblast survival, improving type 1 collagen synthesis and bone strengthening and integrity.[6]

The peptide regulates stem cell differentiation of the bone marrow and osteogenesis (new bone formation) by modulating the TGF-beta/SMAD pathway. In addition to protecting and ensuring the survival of osteoblasts, the peptide promotes their development from stem cells.


How MOTS-c May Promote Heart Health

Research suggests that patients with low MOTS-c levels in their bloodstream are more likely to experience endothelial cell dysfunction.[7] Meanwhile, endothelial cells line the inner walls of blood vessels, regulating blood pressure, forming plaques, and promoting blood clotting. MOTS-c does not directly increase blood vessel responsiveness but indirectly impacts endothelial cells, activating other responsive molecules such as acetylcholine. MOTS-c peptide improves blood vessel function at the microvascular, endothelial, and epicardial levels.

Research further suggests that MOTS-c may play an active role in protecting heart cells against inflammation, stress, and reperfusion injury.[8]

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  1. Lu H, Wei M, Zhai Y, et al. MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction. J Mol Med (Berl). 2019;97(4):473-485. doi:10.1007/s00109-018-01738-w.
  2. Kim KH, Son JM, Benayoun BA, Lee C. 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.e7. doi:10.1016/j.cmet.2018.06.008.
  3. Kim SJ, Miller B, Mehta HH, et al. The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity. Physiol Rep. 2019;7(13):e14171. doi:10.14814/phy2.14171.
  4. 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. doi:10.1016/j.freeradbiomed.2016.05.015.
  5. Fuku N, Pareja-Galeano H, Zempo H, et al. The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity?. Aging Cell. 2015;14(6):921-923. doi:10.1111/acel.12389.
  6. Crescenzo R, Bianco F, Mazzoli A, Giacco A, Liverini G, Iossa S. A possible link between hepatic mitochondrial dysfunction and diet-induced insulin resistance. Eur J Nutr. 2016;55(1):1-6. doi:10.1007/s00394-015-1073-0.
  7. Qin Q, Delrio S, Wan J, et al. Downregulation of circulating MOTS-c levels in patients with coronary endothelial dysfunction. Int J Cardiol. 2018;254:23-27. doi:10.1016/j.ijcard.2017.12.001.
  8. Yang Y, Gao H, Zhou H, et al. The role of mitochondria-derived peptides in cardiovascular disease: Recent updates. Biomed Pharmacother. 2019;117:109075. doi:10.1016/j.biopha.2019.109075.