MOTS-c (Mitochondrial-derived Peptide)

The MOTS-c peptide (Mitochondrial Open Reading Frame of the 12S rRNA-c) is a novel mitochondrial-derived peptide. It is a short peptide composed of 16 amino acids, expressed in tissues and plasma, indicating a specific cellular and hormonal role.(1) With the potential to function as both a cell-specific compound and a hormone, this peptide possibly acts by stimulating the AMP-activated protein kinase (AMPK) pathway. Only two mitochondrial-derived peptides (MDPs) have been studied, Humanin and MOTS-c. When metabolic stress occurs in the organism, the peptide is believed to translocate to cell nuclei and alter gene expression. The MOTS-c peptide may also be released extracellularly and is known as a "mitochondrial hormone" or simply as a "mitokine."(2)(3)

Chemical Composition(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

Animal research models have indicated multiple potential actions of the MOTS-c peptide, including increased physical performance, regulated cellular and tissue metabolism, and myoblast adaptation.(2) Research suggests that these actions may depend primarily on age and age-related changes in MOTS-c expression. Researchers suggest that MOTS-c levels and activity might decrease, suggesting a role in the cellular aging process and the development of age-related metabolic dysfunction. Additionally, MOTS-c may interact with known aging regulators, such as NAD+ and sirtuins, suggesting its involvement in pathways that potentially modulate cell lifespan.(1) According to Joseph C Reynolds et al., “Mitochondria are major metabolic organelles with strong implications in cellular aging that also coordinate broad physiological functions, in part, using peptides that are encoded within their independent genome.”(5) It has also been postulated that endogenous expression of the peptide is driven through physical activity, potentially improving cellular metabolism.(5)

With increasing age, skeletal muscles tend to gain insulin resistance, leading to decreased glucose uptake. Upon exposure to the peptide, skeletal muscles may be stimulated with an improved response towards AMPK activation. As a result, glucose transporter expression may increase, potentially improving skeletal muscle metabolism and enhancing skeletal muscle functioning and growth. Furthermore, it is postulated that MOTS-c actions include targeting metabolic pathways such as the folate-methionine cycle and purine biosynthesis. This targeting can potentially lead to modulation of cellular metabolism, including actions on glucose uptake and lipid utilization. The peptide's impact could involve a shift in metabolic priorities within the cell, possibly affecting the balance between anabolic and catabolic processes. In systemic metabolism, it is postulated that MOTS-c functions as a mitochondrial hormone, and circulating peptide levels appear to affect metabolic functions in skeletal muscle and possibly adipose tissue. Its potential regulatory actions on glucose homeostasis and insulin action suggest a broader hormonal role in energy balance and nutrient sensing across different tissues.(1)

Research has suggested that the peptide may potentially leave the mitochondrial site, translocate to cell nuclei, and possibly alter gene expression. More specifically, the peptide may interact with a wide range of genes, particularly those with antioxidant response elements (ARE), suggesting a possible regulatory relationship with stress-sensitive transcription factors such as NRF2. Such findings suggest a genetically integrated mitonuclear communication system, where both mitochondrial and nuclear genomes may encode factors that co-regulate each other. This action, in turn, may alter glucose uptake restriction.(6) This hypothesis was first suggested in a study where experimental mice were given high-fat feed, and only half were presented with the peptide. Researchers indicated that MOTS-c can potentially affect cellular metabolism by inhibiting the folate cycle directly tied to de novo purine biosynthesis, which consequently leads to AMPK activation. Such actions suggest a broader role of the peptide in regulating insulin sensitivity and metabolic homeostasis, offering insights into its preventive potential against age-dependent and fat-induced insulin resistance and diet-induced obesity. The study presents supporting data to suggest that the peptide may stimulate glucose utilization, affect the methionine-folate cycle, and promote AMPK activation. These cellular actions suggest that MOTS-c could coordinate various metabolic processes, including glucose and lipid metabolism. Consequently, murine models exposed to the peptide were lean and more energetic than the rest, further indicating that the peptide might prevent fat accumulation and induce glucose uptake via the AMPK pathway.(3)

It has been suggested that the MOTS-c peptide regulates the transforming growth factor beta (TGF-beta)/SMAD pathway, which can profoundly affect bone tissues.(7) More specifically, MOTS-c actions may involve upregulation of genes related to the TGF-β/Smad pathway, including TGF-β1, TGF-β2, and Smad7, suggesting a pivotal role of this pathway in MOTS-c-mediated osteogenic differentiation. This hypothesis is further supported when MOTS-c-promoted osteogenic differentiation is reversed upon TGF-β1 knockout, indicating that MOTS-c actions may be mediated at least in part via the TGF-β/Smad pathway. The peptide may also stimulate the expression of osteogenesis-related genes such as ALP, Bglap, and Runx2. Thus, this peptide may stimulate the SMAD pathway in osteoblastic cells, possibly improving bone density and strength. When studied in bone marrow cells, this compound appeared to trigger stem cell differentiation, which may lead to bone tissue development.

Researchers have not suggested that the peptide directly influences cardiac function; instead, researchers postulate that the peptide exerts potential on endothelial cells that line blood vessels on the inside. These endothelial tissues are considered to affect blood pressure and clotting. Researchers suspect that a positive correlation exists between MOTS-c levels and microvascular and epicardial endothelial function. Such findings tentatively suggest MOTS-c as a potential biomarker for endothelial function, and the study reveals a nuanced relationship between MOTS-c levels and vascular reactivity. Furthermore, research suggested that when mice were exposed to MOTS-c, it appeared to improve endothelial tissue functioning, thus possibly easing dysfunction. The mechanistic basis for MOTS-c action on endothelial function remains speculative but may involve AMPK activation.(8)

Research has suggested that the peptide may be associated with increased longevity at the cellular level. The peptide generally contains glutamate residues, but when this is replaced by lysine, the new compound may exert a functional change. Scientists so far know that the functionality of glutamate and lysine groups is vastly different, but it is not yet understood how this specific structural change affects peptide functionality. Noriyuki Fuku et al. suggests that there is “a biological link between MOTS-c and extended lifespan through the purported endocrine action of this mitokine. Further mechanistic research is needed to determine the functional significance of the polymorphism and the potential influence of MOTS-c on the [...] aging process.”(9)