MOTS-C 40mg

MOTS-c (Mitochondrial ORF of the 12S rRNA type-c) is a small mitochondrial-derived peptide composed of 16 amino acids encoded by the mitochondrial 12S rRNA gene. Unlike traditional proteins encoded by nuclear DNA, MOTS-c is synthesized from the mitochondrial genome and acts as a metabolic regulator. It plays a key role in cellular stress responses, glucose metabolism, and insulin sensitivity. MOTS-c has shown promising effects in aging, obesity, and metabolic diseases due to its ability to enhance energy homeostasis and protect against metabolic stress.

Introduction:

The discovery of mitochondrial-de3rived peptides (MDPs) has opened new frontiers in understanding cellular energy regulation and inter-organelle communication. Among these, MOTS-c has emerged as a particularly significant peptide due to its multifaceted role in metabolic homeostasis. Encoded by a short open reading frame within the mitochondrial 12S rRNA gene, MOTS-c represents a paradigm shift in mitochondrial function, extending its role beyond bioenergetics to include direct regulation of nuclear gene expression and systemic metabolism.

Unlike traditional mitochondrial outputs such as ATP or reactive oxygen species, MOTS-c functions as a hormone-like signal that translocates to the nucleus under metabolic stress, where it modulates transcriptional programs involved in energy balance. Early studies have demonstrated that MOTS-c improves insulin sensitivity, promotes glucose utilization, and protects against diet-induced obesity and insulin resistance in animal models. Additionally, it plays a vital role in adaptive stress responses, aging, and possibly cognition and muscle regeneration.

Given its unique origin, potent systemic effects, and therapeutic potential, MOTS-c is attracting increasing attention in the fields of endocrinology, gerontology, and metabolic research. Understanding its functions and mechanisms may pave the way for novel interventions in age-related and metabolic diseases.

Overview

MOTS-c is a mitochondrial-derived peptide that exemplifies the emerging concept of mitochondrial-nuclear communication via bioactive peptides. It is composed of 16 amino acids and encoded by a short open reading frame (sORF) within the mitochondrial 12S rRNA gene, which is highly conserved across species. Unlike traditional nuclear-encoded peptides, MOTS-c is translated from mitochondrial RNA and participates in cellular signaling pathways that extend well beyond the mitochondria.

One of the hallmark features of MOTS-c is its ability to translocate to the nucleus in response to metabolic stress, such as glucose restriction or oxidative stress. Upon nuclear entry, it modulates the expression of genes associated with metabolism, stress resistance, and cell survival. This process involves interaction with transcription factors like NRF2 and AMPK-related signaling pathways, which are central to cellular adaptation under energy-deprived conditions.

MOTS-c plays a crucial role in glucose homeostasis by promoting glucose uptake and glycolysis, while simultaneously inhibiting the accumulation of fat. It enhances insulin sensitivity and reduces insulin resistance, making it a promising candidate for managing conditions like type 2 diabetes and metabolic syndrome. In rodent models, administration of MOTS-c led to improved glucose tolerance, reduced body weight, and increased energy expenditure.

Its influence on muscle physiology is also significant. MOTS-c levels decline with age, and its supplementation has been shown to enhance skeletal muscle function and endurance in aged mice. This suggests a role in mitigating age-related sarcopenia and promoting mitochondrial biogenesis. Furthermore, by activating AMPK, MOTS-c mimics the effects of exercise at the molecular level, earning it the label of an “exercise mimetic” in some studies.

In addition to its metabolic benefits, MOTS-c exhibits cytoprotective properties. It protects cells from oxidative damage and apoptosis through mitochondrial pathways and may contribute to lifespan extension under certain conditions. Recent research is exploring its neuroprotective potential, given that metabolic dysfunction and mitochondrial impairments are common features in neurodegenerative disorders.

What distinguishes MOTS-c from other peptides is its systemic endocrine-like activity despite being of mitochondrial origin. It circulates in the bloodstream and exerts effects on distant tissues, indicating a hormonal function. Its ability to bridge mitochondrial signals to nuclear gene regulation places it at the intersection of metabolism, aging, and stress adaptation.

Therapeutically, MOTS-c represents a promising avenue for treating metabolic disorders, age-related muscle loss, and possibly even cognitive decline. Synthetic analogs of MOTS-c are being explored for clinical development due to their stability and efficacy in preclinical trials.

In conclusion, MOTS-c is not only a novel mitochondrial product but also a key regulatory molecule in systemic physiology. Its discovery has redefined mitochondrial biology and opened new strategies for targeting metabolic and age-associated diseases.

Mechanism of action

MOTS-c (Mitochondrial ORF of the 12S rRNA type-c) exerts its physiological effects through multi-level metabolic regulation, integrating mitochondrial signaling, nuclear gene modulation, and cellular stress response pathways. Its mechanism of action involves the following key steps:

1. Mitochondrial Stress Sensing and Cytoplasmic Release

MOTS-c is encoded by a small open reading frame (sORF) within the mitochondrial 12S rRNA. Under conditions of metabolic stress (e.g. glucose deprivation, oxidative stress), MOTS-c is synthesized within the mitochondria and translocates into the cytoplasm, initiating downstream signaling cascades.

2. Nuclear Translocation and Gene Regulation

Upon cellular energy stress, MOTS-c moves from the cytoplasm to the nucleus, where it interacts with nuclear transcription factors such as NRF2 (Nuclear Factor Erythroid 2–related Factor 2). This interaction enhances the transcription of antioxidant response genes and metabolic genes involved in glucose metabolism, mitochondrial function, and stress resistance.

3. Activation of AMPK Pathway

MOTS-c strongly activates AMP-activated protein kinase (AMPK), a central regulator of cellular energy balance. This leads to:

• Increased glucose uptake by upregulating GLUT4 transporters
• Enhanced fatty acid oxidation
• Inhibition of anabolic pathways (e.g. mTOR) to conserve energy
• Improved mitochondrial biogenesis via PGC-1α activation

AMPK activation by MOTS-c mimics the effects of exercise and caloric restriction, improving metabolic flexibility and insulin sensitivity.

4. Inhibition of Folate Cycle to Regulate One-Carbon Metabolism

MOTS-c also inhibits the folate cycle by targeting methylenetetrahydrofolate dehydrogenase (MTHFD), which decreases de novo purine biosynthesis. This creates a mild purine depletion, activating AMPK as a secondary response. This novel mechanism links nucleotide metabolism with energy sensing.

5. Systemic Endocrine-Like Effects

Although mitochondrial in origin, MOTS-c is found in the circulation, acting in an endocrine-like fashion. It influences distant tissues such as:

• Muscle: Enhancing performance and insulin sensitivity
• Adipose tissue: Promoting fat oxidation
• Liver: Reducing gluconeogenesis and lipid accumulation

Summary Flow:

Mitochondrial stress → MOTS-c synthesis → Nuclear entry → AMPK activation → Metabolic gene regulation → Enhanced stress resilience and energy metabolism

Structure

Aminoacid Sequence: Met-Arg-Trp-Gin-Glu-Met-Gly-Tyr-lle-Phe-Tyr-Pro-Arg-Lys-Leu-Arg

Molecular Formula: C₁₀₁ H₁₅₂.N₂₈O₂₂,S₂.

Molecular Weight: 2174.64 g/mol

PubChem SID: 255386757

CAS Number: 1627580-64-6

Synonyms: Mitochondrial open reading frame of the 12S RNA-c, MT-RNR1

Research

Muscle metabolism

MOTS-c plays a significant role in regulating skeletal muscle metabolism, particularly under conditions of metabolic stress and aging. It influences key pathways associated with energy homeostasis, mitochondrial function, and exercise adaptation, thereby enhancing muscle function and resilience.

1. Activation of AMPK Pathway in Muscle MOTS-c activates AMP-activated protein kinase (AMPK), a crucial energy sensor in muscle cells. AMPK activation leads to:
   • Increased glucose uptake via GLUT4 translocation
   • Enhanced fatty acid oxidation
   • Inhibition of anabolic pathways (e.g., mTOR), which promotes energy conservation during exercise or stress These effects contribute to improved muscle endurance, energy efficiency, and insulin sensitivity (Lee C et al., 2015).
2. Enhancement of Mitochondrial Biogenesis MOTS-c induces PGC-1α, a master regulator of mitochondrial biogenesis, promoting the formation of new mitochondria and improving oxidative capacity in skeletal muscles. This supports better energy production and resistance to fatigue (Reynolds JC et al., 2021).
3. Exercise Mimetic Effects MOTS-c mimics certain molecular aspects of physical exercise. In animal studies, administration of MOTS-c improved muscle performance and physical capacity without actual physical training, which is particularly beneficial for aging or immobilized individuals (Lu H et al., 2019).
4. Prevention of Age-Related Muscle Decline (Sarcopenia) Age-related decline in MOTS-c levels correlates with muscle loss and weakness. Supplementation restores muscle metabolic flexibility and protects against sarcopenia in aged mice, possibly by improving protein turnover and enhancing insulin signaling in muscle tissues (Reynolds JC et al., 2021).
5. Insulin Sensitivity and Glucose Metabolism In skeletal muscle, MOTS-c improves insulin sensitivity by enhancing glucose transport and reducing intramuscular fat accumulation, which is key for preventing insulin resistance and type 2 diabetes (Kim KH et al., 2018).

Fat metabolism

MOTS-c plays a critical role in fat metabolism by modulating energy balance, enhancing lipid utilization, and preventing fat accumulation. Its effects are mediated through mitochondrial signaling, activation of metabolic regulators, and endocrine-like functions across key tissues such as adipose tissue, liver, and skeletal muscle.

1. Enhancement of Lipid Oxidation

MOTS-c stimulates fatty acid oxidation in multiple tissues by activating AMP-activated protein kinase (AMPK), a central energy-sensing enzyme. AMPK activation leads to:

• Suppression of acetyl-CoA carboxylase (ACC) activity
• Reduction in malonyl-CoA, an inhibitor of carnitine palmitoyltransferase-1 (CPT1)
• Increased mitochondrial uptake and oxidation of fatty acids These processes reduce lipid accumulation and enhance overall lipid metabolism (Lee C et al., 2015).

2. Reduction of Adiposity and Lipid Storage

In animal studies, chronic MOTS-c treatment prevents diet-induced obesity by reducing fat mass without affecting food intake. This is partly due to increased thermogenic activity and energy expenditure, possibly through upregulation of uncoupling proteins (UCPs) in adipose tissue (Reynolds JC et al., 2021).

3. Improvement of Insulin Sensitivity in Adipose Tissue

MOTS-c improves insulin signaling in adipocytes, facilitating glucose uptake and lipolysis. Enhanced insulin sensitivity reduces lipogenesis (fat creation) and promotes lipolysis (fat breakdown), further supporting anti-obesity effects (Kim KH et al., 2018).

4. Regulation of Adipokines and Inflammatory Markers

MOTS-c modulates the expression of adipokines (e.g., adiponectin) and reduces inflammatory cytokines like TNF-α and IL-6, which are known to disrupt lipid metabolism and promote obesity. By creating a healthier adipose environment, MOTS-c supports better fat utilization and metabolic function (Lu H et al., 2019).

5. Prevention of Hepatic Steatosis

MOTS-c also protects against fat accumulation in the liver (hepatic steatosis) by suppressing lipogenesis and promoting fat oxidation. This is crucial for preventing fatty liver disease, a common consequence of metabolic dysfunction (Reynolds JC et al., 2021).

Insulin sensitivity

Role of MOTS-c in Insulin Sensitivity

It significantly enhances insulin sensitivity by modulating metabolic pathways, improving glucose homeostasis, and activating energy-regulating signals. Its insulin-sensitizing effects have been demonstrated in both cellular and animal models, particularly in the context of diet-induced obesity and insulin resistance.

1. AMPK Activation and Glucose Uptake

It activates AMP-activated protein kinase (AMPK), a central regulator of cellular energy homeostasis. AMPK activation enhances:

• Translocation of GLUT4 transporters to the cell membrane in skeletal muscle and adipose tissue
• Increased glucose uptake independent of insulin
• Improved insulin signaling efficiency, especially in insulin-resistant conditions (Lee C et al., 2015)

2. Suppression of Mitochondrial Stress and Inflammation

It reduces oxidative stress and pro-inflammatory cytokines (e.g., TNF-α, IL-6), both of which are known to impair insulin signaling. By maintaining mitochondrial integrity and reducing endoplasmic reticulum stress, MOTS-c helps restore normal insulin receptor activity and downstream signaling (Kim KH et al., 2018).

3. Enhanced Insulin Sensitivity in Animal Models

In high-fat diet-fed mice, MOTS-c administration:

• Improved insulin tolerance test (ITT) performance
• Reduced fasting insulin levels
• Enhanced glucose disposal rate

Despite similar food intake and physical activity, MOTS-c–treated mice showed greater insulin sensitivity than controls, confirming its direct metabolic effects (Lee C et al., 2015).

4. Nuclear Gene Regulation Linked to Insulin Pathways

MOTS-c translocates to the nucleus during metabolic stress and modulates transcription of genes involved in insulin signaling, including IRS-1, PI3K, and AKT pathways. This supports sustained insulin responsiveness under stress conditions (Kim KH et al., 2018).

5. Synergy with Exercise and Caloric Restriction Pathways

It also mimics exercise-induced molecular changes,notably the activation of AMPK and PGC-1α, both of which enhance insulin sensitivity. This suggests its potential as a therapeutic mimetic of exercise for metabolic disorders (Reynolds JC et al., 2021).

Osteoporosis

It shows promising potential in the management of osteoporosis, primarily due to its ability to regulate bone metabolism, reduce oxidative stress, and improve systemic metabolic health, all of which are key contributors to bone integrity.

1. Promotion of Osteoblast Activity

MOTS-c has been shown to enhance osteoblast differentiation and function, the cells responsible for bone formation. By activating the AMPK pathway, MOTS-c supports energy homeostasis in osteoblasts, allowing them to better synthesize bone matrix and mineralize it effectively (Zhao J et al., 2021).

• AMPK activation also leads to upregulation of RUNX2, a transcription factor essential for osteoblast development.
• It promotes bone anabolic pathways, counteracting the bone-resorptive effects seen in osteoporosis.

2. Inhibition of Osteoclastogenesis

It  may inhibit osteoclast differentiation indirectly by reducing systemic inflammation and oxidative stress, which are known stimulators of osteoclast formation. Osteoclasts break down bone tissue; thus, MOTS-c’s ability to suppress excessive bone resorption contributes to preserving bone mass.

3. Reduction of Oxidative Stress and Mitochondrial Dysfunction

Oxidative stress is a major factor in age-related bone loss. MOTS-c has antioxidant properties and maintains mitochondrial function, both of which help preserve osteocyte viability and bone homeostasis (Kim KH et al., 2018).

• Improved mitochondrial signaling supports the survival of bone-forming cells under stress conditions.
• It also reduces ROS (reactive oxygen species) levels that can trigger bone resorption.

4. Metabolic Health and Bone Cross-talk

By improving insulin sensitivity, reducing fat mass, and enhancing muscle function, MOTS-c indirectly contributes to bone health. There is increasing evidence that metabolic diseases like obesity and diabetes worsen osteoporosis risk; thus, MOTS-c’s broad metabolic benefits support skeletal protection (Lee C et al., 2015).

Role in cardiometabolic health

MOTS-c (Mitochondrial ORF of the 12S rRNA-c) plays a protective and regulatory role in cardiovascular health through multiple mechanisms involving metabolic regulation, oxidative stress reduction, and inflammation control. Recent evidence suggests that MOTS-c may be a promising therapeutic target for preventing and treating cardiovascular diseases (CVD), especially in aging and metabolic syndromes.

1. Protection Against Ischemic Injury

It has been shown to reduce myocardial damage in experimental models of ischemia-reperfusion injury. It does so by:

• Activating AMPK, which enhances energy production during oxygen deprivation.
• Improving mitochondrial function and ATP availability in cardiomyocytes.
• Suppressing cell death pathways (e.g., apoptosis) associated with reperfusion injury (Zhang Y et al., 2021).

2. Reduction of Oxidative Stress

Cardiac tissues are highly sensitive to oxidative stress, a key factor in heart failure and atherosclerosis. MOTS-c:

• Decreases ROS (reactive oxygen species) levels.
• Enhances expression of antioxidant genes via NRF2 activation.
• Helps maintain redox homeostasis in cardiomyocytes (Kim KH et al., 2018).

3. Anti-inflammatory Effects

Chronic inflammation is a known contributor to vascular dysfunction and atherosclerosis. MOTS-c has been shown to:

• Reduce circulating pro-inflammatory cytokines (e.g., TNF-α, IL-6).
• Inhibit NF-κB signaling, a central pathway in vascular inflammation (Lee C et al., 2015).
• Protect endothelial cells from inflammatory damage, improving vascular function.

4. Improvement in Metabolic Cardiac Health

Metabolic diseases such as obesity and insulin resistance contribute to cardiac dysfunction. By improving insulin sensitivity and reducing lipid accumulation, MOTS-c helps:

• Prevent cardiac steatosis (fat deposition in the heart).
• Enhance cardiac glucose utilization, especially under stress or in diabetic hearts.
• Support cardiac contractility and output through efficient energy metabolism (Reynolds JC et al., 2021).

5. Support of Vascular Function and Blood Pressure Regulation

MOTS-c may have indirect benefits on blood pressure and vascular tone by:

• Enhancing endothelial nitric oxide synthase (eNOS) activity.
• Promoting vasodilation through AMPK-mediated pathways.
• Preserving vascular compliance in aging or diseased vessels (Lu H et al., 2023)

References

1. 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(3):443–54.
2. Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12(1):470.
3. Lu H, Buchan RJ, Cook SA. Mitochondrial peptides: a new class of signaling molecules in metabolism. Cell Metab. 2019;30(4):768–80.
4. 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(4):516–24..
5. https://doi.org/10.1016/j.cmet.2015.02.009

6. Zhang Y, Wang Y, Chen X, Wang D, Zhang D. MOTS-c protects against myocardial ischemia/reperfusion injury via activation of AMPK and reduction of oxidative stress. Int J Mol Sci. 2021;22(5):2453.
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;28(4):516–24.
8. 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(3):443–54.
9. Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12(1):470.