MOTS-c Peptide

Introduction

MOTS-c (mitochondrial open reading frame of the 12S rRNA c) is a novel mitochondria-derived peptide composed of 16 amino acids. It was first identified in 2015 and is encoded by a short open reading frame within the mitochondrial 12S rRNA gene. Unlike typical cellular proteins, MOTS-c is encoded in the mitochondrial genome but translated in the cell cytoplasm, highlighting the unique cross-talk between mitochondria and the rest of the cell. This peptide is naturally expressed in various tissues and also circulates in the bloodstream, acting in both a local (cell-specific) and hormone-like manner. Because of this dual role, MOTS-c is often described as a “mitokine” – a mitochondrial-derived signaling molecule that influences cells throughout the body. Research interest in MOTS-c has grown rapidly due to its remarkable effects on metabolism and potential anti-aging benefits, positioning it as a promising candidate in metabolic and longevity science.

Figure: Overview of MOTS-c origins and its multifaceted roles. MOTS-c is encoded in mitochondrial DNA and influences aging, cardiovascular health, metabolic balance (insulin sensitivity and weight control), and inflammation via pathways like AMPK and NRF2. It acts as a hormone-like messenger from mitochondria to the rest of the system, supporting metabolic homeostasis.

Metabolic Effects and Mechanisms

One of the most prominent roles of MOTS-c is regulating cellular metabolism and energy balance. Mechanistically, MOTS-c triggers activation of the cellular energy sensor AMPK (5’ AMP-activated protein kinase), which in turn enhances glucose uptake and utilization in cells. In fact, studies show that MOTS-c promotes the entry of glucose into muscle cells via the AMPK pathway, facilitating glycolysis and overall energy production. This action leads to improved insulin sensitivity: in skeletal muscle, MOTS-c treatment boosts insulin-responsive glucose uptake and utilization, effectively enhancing insulin sensitivity and glucose balance in the body. Notably, MOTS-c was shown to activate the downstream metabolic transporter GLUT4 in muscle, further promoting glucose absorption into tissues. These metabolic benefits translate into whole-body effects: for example, in diet-induced obesity models, MOTS-c administration prevented excessive weight gain and insulin resistance when mice were fed a high-fat diet, without affecting weight in lean diets. Treated mice maintained normal blood glucose and insulin levels despite a fat-rich diet, indicating MOTS-c’s potential to protect against obesity and metabolic syndrome.

On a cellular level, MOTS-c reprograms fuel utilization in ways that favor metabolic health. It can inhibit a key step of the folate cycle (at the level of 5-methyltetrahydrofolate), leading to the accumulation of AICAR – a natural analog of AMP that potently activates AMPK. Through this folate-purine-AMPK pathway, MOTS-c essentially mimics a low-energy state in cells, pushing them to boost catabolic processes for energy balance. At the same time, MOTS-c elevates cellular NAD⁺ levels and engages sirtuin pathways (e.g. SIRT1), which are well-known longevity and metabolic regulators. By favorably influencing the folate/methionine cycle and restricting methionine metabolism, MOTS-c induces a shift in cellular priorities from growth toward maintenance. For instance, research shows MOTS-c drives glucose into the pentose phosphate pathway (for anabolic needs and antioxidant defense) rather than burning it immediately via glycolysis, while simultaneously increasing fatty-acid oxidation by upregulating carnitine shuttle activity in mitochondria. This comprehensive metabolic shift results in enhanced lipid utilization (lower cellular fat accumulation) and an efficient use of nutrients, echoing the metabolic effects of calorie restriction or exercise at the cellular scale. In essence, MOTS-c acts as a metabolic master switch that promotes energy homeostasis: it helps cells take up and use glucose, ramps up fat burning, and avoids metabolic dysfunction under stress conditions.

Muscle Metabolism and Exercise Performance

MOTS-c has a particularly strong influence on skeletal muscle, which is a primary target tissue for its action. In muscle cells, MOTS-c markedly improves insulin signaling and metabolic function. Studies in mice demonstrated that a short course of MOTS-c treatment completely reversed age-related insulin resistance in old muscles – after one week of MOTS-c administration, older mice’s muscles responded to insulin as effectively as those of much younger mice. This outcome was attributed to MOTS-c restoring metabolic balance in muscle tissue (largely via AMPK activation), underscoring its potential for combating age-dependent metabolic decline. In young adult mice on a high-fat diet, MOTS-c also activated muscle AMPK and increased GLUT4 levels, leading to better glucose uptake in muscle and prevention of fat accumulation. Intriguingly, MOTS-c behaves like an exercise mimetic in muscle: it is an exercise-induced peptide, meaning that during physical activity the levels of MOTS-c naturally rise. Human studies have shown that acute exercise can raise MOTS-c levels ~12-fold in skeletal muscle (and about 1.5-fold in circulation), with elevated levels persisting for hours post-exercise. This suggests that MOTS-c helps mediate some benefits of exercise. In laboratory models, giving MOTS-c to sedentary animals produces exercise-like benefits – it activates an “exercise signal” network that increases endurance and muscle capacity. Researchers reported that MOTS-c administration significantly enhanced physical performance in mice across various ages, improving exercise tolerance in not just young but also middle-aged and old mice. These findings have led scientists to propose that MOTS-c triggers mitohormesis, a beneficial stress response akin to exercise, thereby promoting muscle adaptation and resilience. In summary, MOTS-c powerfully supports muscle metabolism by improving insulin sensitivity, boosting glucose and fatty acid utilization, and even mimicking some effects of endurance exercise – a profile that is highly promising for addressing metabolic health and age-related muscle decline.

Fat Metabolism and Weight Management

Beyond muscle, MOTS-c also impacts adipose (fat) tissue metabolism and systemic energy balance. The peptide’s metabolic actions extend to regulating how the body stores or burns fat. In animal studies, MOTS-c treatment kept mice on a high-fat, high-calorie regimen leaner and more energetic compared to untreated counterparts. The treated mice resisted diet-induced obesity, showing lower fat accumulation and better glucose control, which implies MOTS-c can counteract the negative effects of a high-fat diet on weight gain and insulin action. Mechanistically, a key way MOTS-c influences fat metabolism is through its upstream activation of AMPK and downstream effects on gene expression. By inhibiting the folate cycle and de novo purine synthesis, MOTS-c triggers an AMPK-driven shift that encourages the body to burn fuel rather than store it. It also increases the oxidation of fatty acids – for example, raising levels of carnitine shuttle proteins and β-oxidation intermediates in cells – which means more fats are transported into mitochondria and used for energy instead of accumulating. In essence, MOTS-c sends a signal to cells to increase energy expenditure and reduce excess fat storage.

Interestingly, MOTS-c’s effects are not limited to metabolism within mitochondria; it can also influence the nucleus of the cell to alter gene activity. Research suggests that under conditions of metabolic stress (such as overeating or oxidative stress), MOTS-c translocates from the mitochondria to the cell nucleus in an AMPK-dependent manner. Once in the nucleus, it binds to specific transcription factors and DNA elements – particularly antioxidant response elements (ARE) that are regulated by the stress-responsive factor NRF2. Through this mechanism, MOTS-c can turn on a suite of stress-defense and metabolic genes that help cells adapt to high-fat stress or insulin resistance. This mitonuclear communication ensures that mitochondrial status (signaled by MOTS-c) can directly prompt the nucleus to compensate by enhancing antioxidant defenses and metabolic adjustments. For example, one study in mice with diet-induced obesity found that MOTS-c improved insulin sensitivity and glucose uptake partly by modulating the folate-methionine cycle and purine biosynthesis pathways in cells. These pathways are intimately tied to nutrient sensing and fat metabolism, so MOTS-c’s ability to regulate them hints at a broad metabolic reset action. Collectively, MOTS-c helps combat metabolic stress from high fat intake by activating AMPK, reducing lipids in tissues, and fine-tuning gene expression to favor a healthier metabolic profile. Such multifaceted actions position MOTS-c as a compelling molecule of interest for managing obesity and metabolic dysfunction (though currently these effects have been demonstrated in preclinical research models).

Aging and Longevity

MOTS-c has garnered significant attention for its potential anti-aging and longevity-related effects. Endogenous levels of MOTS-c appear to change with age, which provides clues to its role in the aging process. Both animal and human studies indicate that MOTS-c levels tend to decline with advancing age in tissues like skeletal muscle and in circulation. For instance, young individuals have measurably higher circulating MOTS-c compared to middle-aged and elderly individuals. In mice, researchers observed that MOTS-c in muscle and blood drops as the animals age, coinciding with the onset of age-related insulin resistance. Intriguingly, when older mice were given MOTS-c injections to restore their MOTS-c to more youthful levels, it reversed certain aging effects – specifically, it restored insulin sensitivity in aged muscles and improved the animals’ exercise capacity to levels comparable with younger mice. Such findings suggest that MOTS-c might play a contributing role in healthy aging, especially in maintaining metabolic function and physical performance as organisms get older.

On a cellular level, MOTS-c engages with known longevity pathways. As mentioned, it boosts NAD⁺ and activates SIRT1, which are classic mediators of lifespan extension in many model organisms. It also interacts with the NRF2 pathway: studies show that the MOTS-c–NRF2 interaction can increase the expression of protective mitochondrial genes, enhancing the cell’s ability to cope with stress and damage. This upregulation of antioxidant and repair genes by MOTS-c contributes to improved cellular stress resistance – a factor thought to slow down aspects of aging. In support of its pro-longevity profile, researchers have noted that higher MOTS-c levels correlate with healthier aging markers in both animals and humans, implying that maintaining MOTS-c might benefit aging tissues. Additionally, genetic studies have uncovered a fascinating link: a naturally occurring variant of the MOTS-c peptide (in which a single amino acid, glutamate, is replaced by lysine at a certain position) has been associated with exceptional longevity in some populations. This mitochondrial DNA polymorphism, thought to alter MOTS-c’s function slightly, was more frequent in long-lived individuals, hinting that MOTS-c could influence human lifespan. While the exact significance of this variant (sometimes called “E14K”) is still under investigation, it underscores a biological connection between MOTS-c and longevity. Researchers propose that MOTS-c acts as an endocrine-like factor – a mitochondrial hormone – that helps coordinate metabolism and stress responses across the body, thereby affecting the aging process. However, more studies are needed to fully determine how boosting MOTS-c might translate to longevity or age-related health in humans.

Bone Health and Osteogenesis

Beyond metabolism, MOTS-c has shown interesting effects on the skeletal system, suggesting a role in bone health. Bone density and strength typically decrease with age (osteoporosis), and researchers have explored whether MOTS-c could counteract this process. In cellular and animal models, MOTS-c indeed appears to promote bone-forming activity. Notably, it can stimulate the differentiation of bone marrow mesenchymal stem cells into osteoblasts (the cells responsible for building new bone). This osteogenic effect is mediated at least in part through the Transforming Growth Factor beta (TGF-β) and SMAD signaling pathway. MOTS-c was found to upregulate key genes in the TGF-β/Smad pathway (such as TGF-β1, TGF-β2, and Smad7) and increase the expression of bone formation markers like alkaline phosphatase (ALP), osteocalcin, and Runx2 in bone cells. These changes translated into enhanced maturation of osteoblasts and greater production of bone matrix (e.g. Type I collagen) in laboratory experiments. In a mouse model of osteoporosis, treatment with MOTS-c improved bone density and microarchitecture, implying that it helped reverse bone loss or accelerate bone regeneration. Importantly, when researchers blocked TGF-β signaling, the pro-bone benefits of MOTS-c were diminished, confirming that the TGF-β/Smad pathway is crucial to MOTS-c’s action in bone. While these findings are still preliminary, they point to MOTS-c as a potential factor in maintaining bone health. By promoting osteoblast activity and possibly balancing the bone remodeling process, MOTS-c could emerge as a novel target for addressing osteoporosis or age-related bone fragility (pending further research).

Cardiovascular and Endothelial Function

MOTS-c’s influence extends to the cardiovascular system, particularly in the context of vascular health. Endothelial cells, which line the inside of blood vessels, play a key role in regulating blood pressure, blood flow, and clotting – and they too appear to be positively affected by MOTS-c. Preliminary clinical research found that individuals with coronary endothelial dysfunction (an early sign of atherosclerosis where blood vessels don’t dilate properly) had significantly lower circulating MOTS-c levels compared to healthy individuals. This observation hints that higher MOTS-c might correlate with better endothelial function, whereas a deficiency in MOTS-c could be linked to vascular problems. In experimental studies, MOTS-c has demonstrated protective effects on blood vessels. For example, exposing endothelial cells to MOTS-c in vitro attenuated dysfunction caused by oxidative stress, in part by activating AMPK and suppressing inflammatory pathways (such as the MAPK/NF-κB pathway) in those cells. In mice, administration of MOTS-c improved markers of endothelial performance, suggesting that it can enhance vascular reactivity and health. These effects make sense given MOTS-c’s known ability to increase nitric oxide bioavailability (through AMPK) and reduce inflammation, both of which are critical for healthy blood vessels. Additionally, emerging studies on the heart have shown that MOTS-c may protect cardiac tissue under stress. Researchers have reported that MOTS-c treatment prevented the development of heart failure in a mouse model, an effect attributed to AMPK activation in the heart muscle and improvements in mitochondrial function. In fact, the benefits of MOTS-c on the heart were likened to those of aerobic exercise – improving cardiac energy metabolism, reducing pathological remodeling, and enhancing angiogenesis (formation of new blood vessels) in cardiac tissue. While the heart-specific targets of MOTS-c are still being investigated, these findings open the door to the peptide’s potential use in supporting cardiovascular health. In summary, by bolstering endothelial function and possibly mimicking exercise-like effects on the heart, MOTS-c shows promise as a factor that could contribute to cardiovascular well-being.

Conclusion

MOTS-c is a cutting-edge mitochondrial peptide that bridges the gap between metabolism and longevity science. Its multifaceted actions – from activating AMPK and improving glucose control to enhancing stress resistance and tissue repair – make it a unique biological regulator with broad therapeutic potential. Research to date highlights MOTS-c’s ability to promote metabolic homeostasis (improving insulin sensitivity, encouraging fat utilization, and preventing diet-induced metabolic disorders) as well as its potential to mitigate aspects of aging (preserving muscle function, bone density, vascular health, and more). These compelling findings have positioned MOTS-c as an exciting focus of study in the fields of metabolic disease and geroscience. However, it is important to note that all current insights into MOTS-c come from laboratory and animal research. MOTS-c peptide is available for research and laboratory use only, and any future applications in medicine or human health will require thorough clinical investigation. Nonetheless, the growing body of evidence on MOTS-c provides a strong scientific foundation and a sense of confidence for researchers exploring new strategies to combat metabolic decline and age-related dysfunction. In the realm of advanced biochemistry and anti-aging research, MOTS-c stands out as a promising molecule that could unlock novel approaches to enhancing healthspan and metabolic vitality.

Sources: The information above is derived from recent scientific literature and studies on MOTS-c, including peer-reviewed research articles and reviews that investigate the peptide’s functions in metabolism and aging. These include findings published in journals such as Cell Metabolism, Nature Communications, Frontiers in Endocrinology, and others, which document MOTS-c’s discovery, mechanisms of action, and potential benefits in various experimental models.

References

1. Lee, C. et al. (2015). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism 21(3):443-454. [doi.org]
2. Kim, K.H. et al. (2018). The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell Metabolism 28(3):516-524. [doi.org]
3. Reynolds, J.C. et al. (2021). MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications 12:470. [doi.org]
4. Zheng, Y., Wei, Z., & Wang, T. (2023). MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. Frontiers in Endocrinology 14:1120533. [doi.org]
5. Wan, W. et al. (2023). Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. Journal of Translational Medicine 21:885. [doi.org]
6. Yi, X. et al. (2023). Role of MOTS-c in the regulation of bone metabolism. Frontiers in Physiology 14:1149120. [doi.org]
7. MedChemExpress (MCE). MOTS-c (human) acetate product information and research data. ChemBK Database. [chembk.com]