Understanding MOTS-c Peptide 

MOTS-c is a mitochondrial peptide that is composed of sixteen amino acids and is encoded by the mitochondrial genome.  This "power generator" in the cell is the mitochondria, which are responsible for converting the chemical energy that is obtained from food into a form that the cell can use for muscle metabolism.  Humanin and SHLP1-6 are two more mitochondria-derived peptides (MDPs) that have been found up to this point; however, it is not known whether or not they have a role in the enhancement of human performance.  Bioactive peptides that are produced from mitochondria, such as MOTS-c, have been shown to play a role in the maintenance of mitochondrial function and the protection of cells from various stresses, according to the most recent research1.  It has been demonstrated that physical activity leads to an increase in mitochondrial-encoded MOTS-c levels in human beings.  Furthermore, it has been demonstrated in mice that treatment with MOTS-c improved physical performance in mice of all ages and appears to affect the metabolism of skeletal muscle as well as gene expression1.  

Mechanism of Action of MOTS-c Peptide

The role of MOTS-c is a crucial regulator of energy homeostasis and is significantly linked to the metabolism of amino acids, carbohydrates, and lipids.  In mammalian cells, it is encoded by mitochondrial DNA and, under stress conditions, translocates to the nucleus, accompanied by increased ROS generation.  The nuclear translocation of MOTS-c is dependent on 5′-adenosine monophosphate-activated protein kinase (AMPK).  MOTS-c also induces the activation of AMPK and the buildup of 5-aminomidazole-4-carboxamide ribonucleotide (AICAR), a recognized AMPK activator, by blocking the folate cycle and de novo purine production.  

AMPK serves as the primary sensor and essential regulator of cellular metabolism in relation to energy availability.  When the ATP:ADP or ATP:AMP ratios increase, AMPK is activated, leading to a shift in metabolism that promotes catabolism and inhibits anabolism through the phosphorylation of essential proteins in many pathways, including mTOR complex 1 (mTORC1). Furthermore, under stress conditions, AMPK directly phosphorylates Peroxisome proliferator-activated receptor Gamma Co-activator-1α (PGC-1α) to activate it.  PGC-1α governs the expression of mitochondrial antioxidants and is a crucial element in mito-nuclear communication.  It may engage with Nuclear Factor, Erythroid -1 and -2 (NRF-1/2) to inhibit mitochondrial oxidative stress, facilitate the removal of impaired mitochondria, and augment mitochondrial biogenesis.

The protective effect of MOTS-c modulates several genes within the nucleus in response to metabolic dysfunction, including those with antioxidant response elements (ARE).  It engages with ARE-regulating stress-responsive transcription factors, including Nuclear Factor Erythroid 2-Related Factor 2 (NFE2L2/NRF2).  NFE2L2/NRF2 is a transcription factor that responds to reactive oxygen species (ROS) and safeguards cells during oxidative stress.  The activation of the NRF2/ARE pathway serves as an antioxidative effect in the treatment of acute kidney damage and vascular dysfunction.  NRF2 notably interacts with AMPK and can modulate MOTS-c-associated metabolic pathways.  The MOTS-c/NRF2 interaction enhances mitochondrial protective genes, and the overexpression of MOTS-c amplifies NRF2 signaling.  [2]

Research Evidence

Aging and MOTS-c

MOTS-C is an exercise-induced mitochondrial-encoded peptide whose metabolic level which is gradually disordered, is one of the indications of aging, which means age-dependent physical decline and muscle. This level of disorder inhibits the normal physiological function of the body and even causes individuals to lose the ability to take care of themselves independently. In point of fact, one of the most important risk factors for chronic diseases is becoming older. In order for an organism to maintain its health, it is essential for its cellular responses to be able to adapt to the ever-changing internal and external settings. In addition to producing a significant quantity of cellular energy, mitochondria are strongly associated with the process of aging, with exercise-induced mitochondrial-encoded regulator of age-dependent physical decline; however, the mechanism that underlies this phenomena suggest that MOTS-C expression is not fully understood. [3]

MOTS-c and Cardiovascular Disease

One of the most significant contributors to cardiovascular issues is obesity.  It was demonstrated through clinical research that roughly one-third of those who were significantly obese suffered from heart failure.  Additionally, as the length is extended, the prevalence rate will steadily increase, and after thirty years, the prevalence rate will be greater than ninety percent.  In addition, obesity would result in the remodeling and dysfunction of the ventricles, which would ultimately lead to the destruction of the structure and physiological function of the heart, which would eventually result in heart failure.  Research revealed that MOTS-C treatment significantly shows an increasing body of research has demonstrated that there is a tight connection between MDP and the factors mentioned above. Furthermore, MDP has been found to improve the pathological response of cardiovascular disease (CVD) through a variety of different mechanisms. [7]

MOTS-c and Insulin-Resistance

The development of insulin resistance can result in a reduction in the number of mitochondria in tissue cells as well as an irregular morphology of these mitochondria, which in turn makes it more difficult to produce ATP.  According to its description, MOTS-c, a mitochondrial-derived peptide, is a "motion simulator" that regulates glucose metabolism in the body in a systematic manner and has an effect on the function of muscle insulin. [8,9]

Research Applications

It has been claimed that MOTS-c, which is a tiny molecular active peptide, may have potential applications in the treatment of aging, insulin resistance, cardiovascular disease, and inflammation.  It will be of enormous importance to human health and the prevention of a variety of diseases in the future to make use of synthetic biology technologies in order to incorporate plasma MOTS-c into probiotics in order to achieve its accurate and controllable expression. [6]

However, the clinical trial and use of bacterial therapy are severely constrained by the virulence of bacteria as well as their immune response, which cannot be completely controlled.  It is of the utmost importance for researchers to find ways to enhance the medicinal benefits and protective properties of microorganisms.  In the present day, the approaches that are utilized the most frequently are surface-modified bacteria and gene-modified bacteria. Additionally, it has been demonstrated that certain naturally occurring bacteria, such as Lactobacillus (LAB) and Escherichia coli Nissle1917 (EcN), are safe for clinical use.  The utilization of these bacteria as chassis bacteria will result in a significant enhancement in clinical functionality. [4,5]

Future Research Perspectives

Understanding specific molecular features of endogenous MOTS-c is an ongoing work.  To ascertain how MOTS-c exerts its clinical therapeutic effect, further research into the mechanism of cell entry will be crucial.  A number of diseases are anticipated to be treated with MOTS-c as a possible target for treatment development.  Synthetic biology techniques, such as gene editing and genetic engineering, can considerably improve biological activity and deliver MOTS-c directly to the action site, thus further broadening the therapeutic application of MOTS-c.  The subsequent biosafety issue, however, has consistently drawn attention.  The reduction or elimination of genetically modified bacteria's toxicity to the body is a critical scientific issue that requires immediate attention.

References

1. Martinez-Reyes I, Chandel NS. Mitochondrial TCA cycle metabolites control physiology and disease. Nat Commun (2020) 11:102. 

2. Kwasniak-Owczarek M, Kazmierczak U, Tomal A, Mackiewicz P, Janska H. Deficiency of mitoribosomal S10 protein affects translation and splicing in arabidopsis mitochondria. Nucleic Acids Res (2019) 47:11790–806. 

3. Kim SJ, Xiao J, Wan J, Cohen P, Yen K. Mitochondrially derived peptides as novel regulators of metabolism. J Physiol (2017) 595:6613–21. 

4. Lee C, Yen K, Cohen P. Humanin: a harbinger of mitochondrial-derived peptides? Trends Endocrinol Metab (2013) 24:222–8. 

5. 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) 28:516–524e7.

6. Popov LD. Mitochondrial peptides-appropriate options for therapeutic exploitation. Cell Tissue Res (2019) 377:161–5. 

7. Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab (2015) 21:443–54. 

8. Yin X, Jing Y, Chen Q, Abbas AB, Hu J, Xu H. The intraperitoneal administration of MOTS-c produces antinociceptive and anti-inflammatory effects through the activation of AMPK pathway in the mouse formalin test. Eur J Pharmacol (2020) 870:172909. doi: 10.1016/j.ejphar.2020.17290

9. Yang B, Yu Q, Chang B, Guo Q, Xu S, Yi X, et al. MOTS-c interacts synergistically with exercise intervention to regulate PGC-1alpha expression, attenuate insulin resistance and enhance glucose metabolism in mice via AMPK signaling pathway. Biochim Biophys Acta Mol Basis Dis (2021) 1867:166126. doi: 10.1016/j.bbadis.2021.166126  

10. https://pubchem.ncbi.nlm.nih.gov/compound/Mots-c#section=2D-Structure