Mitochondria are the “powerhouse” of the cell due to their role in delivering cellular functions, including but not limited to cellular metabolism, growth and development, and survival activities. However, with increased age, mitochondrial activities naturally weaken. To combat mitochondrial aging, scientists have cited the MOTS-c Peptide, derived from the mitochondria, for its potential to support the body’s ideal functioning. 

Only two mitochondria-derived peptides have been discovered so far, Humanin and MOTS-C peptide, with MOTS-peptide being recently discovered in 2015.⁽¹⁾ MOTS-C (mitochondrial open-reading-frame of the twelve S rRNA -c) peptide is a short peptide containing 16 amino acids, whose sequence is seen below:⁽¹²⁾

The MOTS-c peptide is expressed in various tissues and can be found in the blood and plasma of rodents and humans. So far, scientific research on the peptide has suggested that it may have a functional role at both cellular and hormonal levels.

Mechanism of Action: In metabolic stress in the body (for instance, during exercise and workouts), researchers posit that the MOTS-C peptide moves towards the cellular nuclei and binds with a receptor. While researchers have yet to confirm which receptor the peptide binds with, they hypothesize that this receptor-peptide bond may stimulate gene expression alteration, causing biological effects.⁽³⁾⁽⁴⁾ When the peptide is released in the bloodstream, it may also be referred to as “mitokine” or “mitochondrial hormone” and may trigger several bodily functions upon release.⁽³⁾⁽⁴⁾

MOTS-C Peptide Research

Despite its recent discovery, scientists have taken an interest in the MOTS-c peptide for its proposed ability to affect the body in various ways. Research studies have sought to validate the peptide’s potential in the following areas, as well as others:

• Promote lipid metabolism
• Reverse insulin resistance
• Develop and maintain osteoblast cells
• Maintain cardiac health
• Increase lifespan

 MOTS-c Peptide and Aging

MOTS-C peptide expression appears to be directly dependent on age. As per Joseph C Reynolds et al., “Mitochondria are chief metabolic organelles with strong implications in aging that also coordinate broad physiological functions, in part, using peptides that are encoded within their independent genome.”⁽⁵⁾Studies report that when the MOTS-C peptide was administered in mice aged 2, 12, and 22 months, the physical performance appeared to be significantly enhanced in all three age groups. The researchers also suggested that this peptide may help regulate cellular and tissue metabolism and myoblast adaptation. In humans, MOTS-C appears to be endogenously expressed via exercise, and similar to the results seen in mice, MOTS-C may enhance the body’s physical activity and cellular metabolism.

MOTS-c Peptide and Metabolism

With increasing age, the skeletal muscles tend to gain insulin resistance leading to decreased glucose uptake. Upon MOTS-C peptide administration, the skeletal muscles may be stimulated with an improved response toward AMPK activation. As a result, glucose transporters may have increased expression, causing improved skeletal muscle metabolism and enhanced skeletal muscle functioning and growth.⁽²⁾

MOTS-c and Obesity

Surgery induced Obesity

When one or both ovaries are surgically removed, typically as part of treating an ovarian cyst, traumatic menopause, or other complications, it is known as Ovariectomy. Due to this surgery, estrogen levels drop, causing fat accumulation and reduced energy. Research in this area has suggested that when the MOTS-c peptide is administered, it may promote lipid metabolism and reduce surgery-induced lipid accumulation. The peptide may also stimulate the AMPK pathway, enhancing body energy and insulin sensitivity.⁽⁶⁾ Based on these scientific results, Huanyu Lu et al. state that “MOTS-c is a high potential candidate for chronic treatment of menopausal induced metabolic dysfunction.”

General Obesity

The AMPK pathway is typically induced when the body is energy deficient, as it utilizes the lipid and glucose “stores” to build additional energy. The MOTS-c peptide may trigger the onset of such AMPK pathway, promoting the utilization of excess lipids and protecting the lean body mass. Interestingly, research has suggested that the MOTS-c peptide may even leave the mitochondrial site, translocate to cellular nuclei, and alter gene expression – another pathway that may alter glucose uptake restriction.⁽⁷⁾ This hypothesis is further supported by a research study where experimental mice were given high-fat food, and only half of those were treated with the MOTS-c peptide. Results indicated that the mice treated with MOTS-c peptide were lean and more energetic than the rest. This supports the finding that the peptide may prevent fat accumulation and induce glucose uptake via the AMPK pathway.

MOTS-c Peptide and Osteoporosis

The MOTS-c peptide appears to regulate the transforming growth factor (TGF) beta and SMAD pathway, which may profoundly affect bone health.⁽⁸⁾ The peptide appears to stimulate the SMAD pathway in the osteoblast cells, improving bone health and strength. Conversely, when studied in bone marrow cells, this compound may trigger the differentiation of the stem cells, leading to bone development. These results suggest that the MOTS-C peptide may improve bone strength and health and produce new bones, which are critical in treating osteoporosis.

MOTS-c and Heart Health

The MOTS-C peptide may not directly influence the cardiac muscles; instead, it may affect the endothelial cells lining the blood vessels. These endothelial tissues affect blood pressure and clotting. Studies show that when MOTS-C peptide was administered in mice, it appeared to have improved the functioning of the endothelial tissues, thereby ameliorating the heart’s overall health.⁽⁹⁾

MOTS-c and Insulin Sensitivity

The MOTS-c peptide is associated with insulin sensitivity, but in lean individuals only. This is due to research suggesting that the compound may hold more potential in monitoring the development of insulin insensitivity rather than maintaining the condition.⁽¹⁰⁾ Given this hypothesis, researchers believe that the peptide may be used to monitor prediabetic lean individuals. Any change in the MOTS-c peptide level should demonstrate an early diagnosis of insulin insensitivity.

MOTS-c Peptide and Lifespan

A structural change in the MOTS-c peptide has been associated with enhanced longevity in a specific group of people, especially the Northeast Asian community.⁽¹¹⁾ The peptide typically contains glutamate residue, but when this is replaced by lysine, the new compound may exhibit a functional change in the peptide. Scientists so far are aware that the functionality of the glutamate and lysine group is vastly different, but how this specific structural change affects peptide functionality is yet to be understood. Noriyuki Fuku et al. suggest that there is “a biological link between MOTS-C and extended lifespan through the putative endocrine action of this mitokine. Further mechanistic research is needed to determine the functional significance of polymorphism and the potential influence of MOTS-C in the human aging process.”

Conclusion

MOTS-C peptide is a recently discovered, 16-amino acid-containing peptide that may help regulate metabolic activities, maintain good health, and modulate insulin sensitivity. Studies indicate that the peptide may have several health advantages, such as obesity management, increased energy levels, enhanced skeletal muscle metabolism, improved heart health, and possible longevity. These results make the MOTS-c peptide a fascinating candidate for further research in the therapeutic world.

Since this peptide was only recently discovered, more in-depth studies and clinical trials are yet to be conducted before it is available for human use. Currently, the peptide available in the market is solely for research purposes.

References

1. Mohtashami Z, Singh MK, Salimiaghdam N, Ozgul M, Kenney MC. MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases. Int J Mol Sci. 2022 Oct 9;23(19):11991. doi: 10.3390/ijms231911991. PMID: 36233287; PMCID: PMC9570330. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9570330/
2. Lee C, Kim KH, Cohen P. MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med. 2016 Nov;100:182-187. doi: 10.1016/j.freeradbiomed.2016.05.015. Epub 2016 May 20. PMID: 27216708; PMCID: PMC5116416. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116416/
3. Zahra Mohtashami et al,  MOTS-c, The Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases, International Journal of Molecular Sciences, https://www.mdpi.com/
4. Lee C, Kim KH, Cohen P. MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med. 2016 Nov;100:182-187. doi: 10.1016/j.freeradbiomed.2016.05.015. Epub 2016 May 20. PMID: 27216708; PMCID: PMC5116416. https://pubmed.ncbi.nlm.nih.gov/27216708/
5. 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. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021 Jan 20;12(1):470. https://pubmed.ncbi.nlm.nih.gov/33473109/
6. Lu H, Wei M, Zhai Y, Li Q, Ye Z, Wang L, Luo W, Chen J, Lu Z. MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction. J Mol Med (Berl). 2019 Apr;97(4):473-485. doi: 10.1007/s00109-018-01738-w. Epub 2019 Feb 6. PMID: 30725119. https://pubmed.ncbi.nlm.nih.gov/30725119/
7. 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 Sep 4;28(3):516-524.e7. doi: 10.1016/j.cmet.2018.06.008. Epub 2018 Jul 5. PMID: 29983246; PMCID: PMC6185997. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185997/
8.  Hu BT, Chen WZ. MOTS-c improves osteoporosis by promoting osteogenic differentiation of bone marrow mesenchymal stem cells via TGF-β/Smad pathway. Eur Rev Med Pharmacol Sci. 2018 Nov;22(21):7156-7163. doi: 10.26355/eurrev_201811_16247. PMID: 30468456. https://pubmed.ncbi.nlm.nih.gov/30468456/
9. Qin Q, Delrio S, Wan J, Jay Widmer R, Cohen P, Lerman LO, Lerman A. Downregulation of circulating MOTS-c levels in patients with coronary endothelial dysfunction. Int J Cardiol. 2018 Mar 1;254:23-27. doi: 10.1016/j.ijcard.2017.12.001. Epub 2017 Dec 6. PMID: 29242099. https://pubmed.ncbi.nlm.nih.gov/29242099/
10. Che N, Qiu W, Wang JK, Sun XX, Xu LX, Liu R, Gu L. MOTS-c improves osteoporosis by promoting the synthesis of type I collagen in osteoblasts via TGF-β/SMAD signaling pathway. Eur Rev Med Pharmacol Sci. 2019 Apr;23(8):3183-3189. doi: 10.26355/eurrev_201904_17676. PMID: 31081069. https://pubmed.ncbi.nlm.nih.gov/31081069/
11. Noriyuki Fuku el al., The mitochondrial-derived peptide MOTS-c: A player in exceptional longevity?, http://dx.doi.org/10.1111/acel.12389.
12.  Image reference: National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 146675088, Mots-c. https://pubchem.ncbi.nlm.nih.gov/compound/Mots-c 

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