MOTS-c Peptide

MOTS-c (mitochondrial open-reading-frame of the 12S rRNA-c) is a recently identified mitochondria-derived peptide composed of 16 amino acids. It is expressed in various tissues and detected in plasma, suggesting that it may function both at the cellular level and as a circulating signalling molecule.(1) This dual role has led to the proposal that MOTS-c may act not only locally within cells but also in a hormone-like manner.

The peptide is thought to exert its effects, at least in part, through activation of the AMP-activated protein kinase (AMPK) pathway, which plays a central role in regulating cellular energy balance. Among mitochondrial-derived peptides (MDPs), only a few have been extensively studied, including Humanin and MOTS-c. Under conditions of metabolic stress, MOTS-c is believed to translocate to the cell nucleus, where it may influence gene expression. Additionally, it may be released into the extracellular environment, contributing to its classification as a “mitochondrial hormone” or “mitokine.”(2)(3)

Chemical Makeup(4)

  • Molecular Formula: C101H152N28O22S2

  • Molecular Weight: 2174.64 g/mol

  • Other Titles: Mitochondrial-derived peptide MOTS-c, Mitochondrial open reading frame of the 12S rRNA-c

Research and Clinical Studies

Animal-based research models have suggested that MOTS-c may be associated with a range of biological effects, including enhanced physical performance, regulation of cellular and tissue metabolism, and adaptation of myoblasts (muscle precursor cells).(2) These proposed actions appear to be influenced by age, with researchers indicating that both the levels and activity of MOTS-c may decline over time, potentially linking the peptide to cellular ageing processes and age-related metabolic dysfunction.

Further research suggests that MOTS-c may interact with established regulators of ageing, such as NAD⁺ and sirtuins, indicating a possible role in pathways that influence cellular lifespan and metabolic balance.(1) As noted by Joseph C Reynolds et al., “Mitochondria are chief metabolic organelles with strong implications in cell aging that also coordinate broad physiological functions, in part, using peptides that are encoded within their independent genome.”(4)

Additionally, endogenous expression of MOTS-c has been proposed to increase in response to physical activity, which may contribute to enhanced metabolic function at the cellular level.(5)

MOTS-c Peptide and Muscle Metabolism

With advancing age, skeletal muscle is often associated with increased insulin resistance, resulting in reduced glucose uptake. Exposure to MOTS-c has been proposed to enhance the responsiveness of skeletal muscle through activation of the AMP-activated protein kinase (AMPK) pathway. This activation may lead to increased expression of glucose transporters, potentially improving glucose uptake, metabolic efficiency, and overall muscle function.

MOTS-c is also suggested to influence key metabolic pathways, including the folate–methionine cycle and purine biosynthesis. Through these interactions, the peptide may contribute to broader regulation of cellular metabolism, potentially affecting both glucose utilisation and lipid metabolism. These actions may reflect a shift in cellular energy priorities, influencing the balance between anabolic and catabolic processes.

At a systemic level, MOTS-c is proposed to function as a mitochondrial-derived hormone, with circulating levels potentially impacting metabolic activity in tissues such as skeletal muscle and adipose tissue. Its suggested role in regulating glucose homeostasis and insulin sensitivity indicates that it may participate in coordinating energy balance and nutrient sensing across multiple organ systems.(1)

MOTS-c Peptide and Fat Cell Metabolism

Research has suggested that MOTS-c may translocate from the mitochondria to the cell nucleus, where it could influence gene expression. In particular, the peptide is proposed to interact with genes containing antioxidant response elements (ARE), indicating a potential relationship with stress-responsive transcription factors such as NRF2. These observations point toward a coordinated system of mitonuclear communication, where mitochondrial and nuclear genomes may interact to regulate cellular functions. Through these mechanisms, MOTS-c may also influence processes related to glucose uptake and metabolic regulation.(6)

This hypothesis was supported by studies in which murine models were subjected to a high-fat diet, with only a portion receiving MOTS-c. Researchers suggested that the peptide may affect cellular metabolism by influencing the folate cycle and de novo purine biosynthesis, leading to activation of the AMPK pathway. These actions are thought to contribute to improved insulin sensitivity and overall metabolic balance, particularly under conditions associated with metabolic stress, such as high-fat diets and ageing.

Further findings indicated that MOTS-c may enhance glucose utilisation, modulate the methionine–folate cycle, and promote AMPK activation. Collectively, these effects suggest that the peptide may coordinate multiple aspects of cellular metabolism, including both glucose and lipid handling. In experimental models, subjects exposed to MOTS-c appeared leaner and more active compared to controls, supporting the idea that the peptide may help limit fat accumulation and enhance glucose uptake through AMPK-mediated pathways.(3)

MOTS-c Peptide and Bone

MOTS-c has been suggested to influence the transforming growth factor beta (TGF-β)/SMAD signalling pathway, which plays a significant role in bone biology.(7) More specifically, the peptide may upregulate genes associated with this pathway, including TGF-β1, TGF-β2, and Smad7, indicating a potential involvement in osteogenic differentiation. Supporting this hypothesis, studies have shown that the osteogenic effects attributed to MOTS-c may be diminished when TGF-β1 expression is reduced, suggesting that its actions may be at least partially mediated through the TGF-β/SMAD pathway.

In addition, MOTS-c has been associated with increased expression of genes linked to bone formation, such as alkaline phosphatase (ALP), osteocalcin (Bglap), and Runx2. These markers are commonly involved in osteoblast activity and bone development. Through these mechanisms, the peptide may stimulate SMAD signalling in osteoblasts, potentially contributing to improvements in bone density and structural integrity. Furthermore, studies involving bone marrow cells have indicated that MOTS-c may promote the differentiation of stem cells into bone-forming cells, supporting its proposed role in bone tissue development.

MOTS-c Peptide and Cardiac Function

Researchers have not suggested that MOTS-c directly influences cardiac function. Instead, its proposed effects appear to be centred on endothelial cells, which line the interior of blood vessels and play a key role in regulating blood pressure and clotting processes. Studies have indicated a potential positive correlation between circulating MOTS-c levels and both microvascular and epicardial endothelial function, suggesting that the peptide may serve as a biomarker of vascular health.

Experimental findings in murine models have shown that exposure to MOTS-c may improve endothelial function, potentially supporting vascular responsiveness and reducing dysfunction. While the exact mechanisms underlying these effects remain uncertain, it has been proposed that activation of the AMPK pathway may contribute to MOTS-c’s influence on endothelial activity. These observations highlight a possible role for the peptide in modulating vascular function, although further research is required to confirm these effects and clarify the underlying pathways.(8)

MOTS-c Peptide and Cell Lifespan

Research has suggested that MOTS-c may be associated with enhanced cellular longevity. Structurally, the peptide typically contains a glutamate residue; however, substitution of this residue with lysine may lead to functional changes. While it is recognised that glutamate and lysine possess markedly different biochemical properties, the exact impact of this substitution on the peptide’s activity and function has not yet been fully understood.

Further investigation by Noriyuki Fuku et al. has proposed a potential biological link between MOTS-c and lifespan extension, possibly through its endocrine-like actions as a mitochondrial-derived signalling peptide. As noted by the researchers, there may be “a biological link between MOTS-c and extended lifespan through the putative endocrine action of this mitokine,” although they emphasise that additional mechanistic studies are required to clarify the significance of such structural variations and to better understand the role of MOTS-c in ageing processes.(9)

The peptide is available for research and laboratory purposes only. Please speak to our friendly research team to find out more and for sourcing options.

References:

  1. 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/

  2. Mohtashami Z, Singh MK, Salimiaghdam N, Ozgul M, Kenney MC. 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.

  3. Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015 Mar 3;21(3):443-54.  doi: 10.1016/j.cmet.2015.02.009.  PMID: 25738459; PMCID: PMC4350682.

  4. 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/

  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. 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/

  7. 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/

  8. 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/

  9. Noriyuki Fuku el al., The mitochondrial-derived peptide: A player in exceptional longevity?,  http://dx.doi.org/10.1111/acel.12389.

Dr. Marinov

Dr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.

MOTS-c Peptide