MOTS-c 10mg

What is MOTS-c?

MOTS-c (Mitochondrial Open Reading Frame of the Twelve S rRNA type-c) is a groundbreaking 16-amino-acid mitochondrial-derived peptide (MDP) with the sequence MRWQEMGYIFYPRKLR and an approximate molecular weight of 2174 Da. Discovered in 2015 by Dr. Changhan Lee and colleagues at the University of Southern California, MOTS-c was the first peptide encoded within the mitochondrial genome shown to actively regulate nuclear gene expression — a paradigm-shifting finding in cell biology (Lee et al., 2015).

MOTS-c is encoded by a short open reading frame (sORF) within the mitochondrial 12S rRNA gene (MT-RNR1). Unlike conventional mitochondrial genes that encode subunits of the electron transport chain, MOTS-c functions as a signaling peptide that is translated in the cytoplasm and can be detected in circulation, acting as a systemic hormone. It belongs to the family of mitochondrial-derived peptides alongside humanin and the small humanin-like peptides (SHLPs), though MOTS-c is unique in its metabolic regulatory functions (Lee et al., 2016). Circulating MOTS-c levels have been shown to decline with age, correlating with age-dependent metabolic deterioration. This peptide represents an exciting frontier in anti-aging peptide research and mitochondrial biology.

Mechanism of Action

MOTS-c exerts its biological effects through a multi-layered mechanism that integrates metabolic regulation, stress response, and retrograde mitochondrial-to-nuclear signaling. Research has revealed that this peptide operates primarily through the folate-AICAR-AMPK pathway, positioning it as a potent metabolic regulator (Lee et al., 2015).

Folate Cycle Inhibition and AMPK Activation

At the cellular level, MOTS-c inhibits the folate cycle and its tethered de novo purine biosynthesis pathway. This inhibition leads to the accumulation of the intermediate metabolite AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), which is a well-established endogenous activator of AMP-activated protein kinase (AMPK). Once activated, AMPK functions as a master metabolic switch, promoting catabolic processes such as glucose uptake, fatty acid oxidation, and mitochondrial biogenesis while inhibiting anabolic pathways including lipogenesis and gluconeogenesis (Wan et al., 2023).

Nuclear Translocation and Gene Regulation

A landmark discovery in 2018 demonstrated that MOTS-c can dynamically translocate from the cytoplasm to the nucleus in response to metabolic stress, including glucose restriction and oxidative stress (Kim et al., 2018). This translocation is AMPK-dependent and represents the first documented case of a mitochondrial-encoded peptide directly regulating nuclear gene expression. In the nucleus, MOTS-c interacts with stress-responsive transcription factors, including NFE2L2/NRF2, and binds to chromatin at genes containing antioxidant response elements (ARE). This enables MOTS-c to coordinate a broad adaptive stress response, regulating genes involved in metabolism, proteostasis, and antioxidant defense.

Downstream Metabolic Effects

Through AMPK activation, MOTS-c promotes the expression of PGC-1α, a key regulator of mitochondrial biogenesis. It enhances glucose transporter (GLUT4) translocation to the cell surface in skeletal muscle, improving glucose uptake independent of insulin signaling. Additionally, MOTS-c activates the SIRT1 pathway, further promoting metabolic homeostasis and anti-inflammatory effects. Studies also indicate that MOTS-c can modulate the AKT signaling pathway, inhibiting upstream transcription factors for myostatin, thereby protecting against muscle atrophy (Kumagai et al., 2021). This complex, multi-pathway mechanism distinguishes MOTS-c from single-target metabolic interventions and makes it a compelling subject for metabolic and aging research.

Research Applications

MOTS-c has emerged as one of the most extensively studied mitochondrial-derived peptides, with research applications spanning metabolic health, exercise physiology, aging, and bone metabolism. Below are the primary research domains where MOTS-c has demonstrated significant effects.

Metabolic Health and Insulin Sensitivity

The foundational study on MOTS-c demonstrated its ability to prevent both age-dependent and high-fat-diet-induced insulin resistance in murine models. Mice treated with MOTS-c showed significantly improved glucose tolerance and insulin sensitivity, with the primary target organ being skeletal muscle (Lee et al., 2015). Research further indicates that MOTS-c enhances glucose metabolism by activating AMPK in skeletal muscle, promoting glucose uptake and fatty acid oxidation. These findings have positioned MOTS-c as a molecule of interest alongside other metabolic peptides such as IPP-1 SM and AOD-9604 in weight loss and metabolic research.

Exercise Physiology and Physical Performance

A landmark 2021 study published in Nature Communications demonstrated that MOTS-c is an exercise-induced peptide that significantly enhances physical performance across age groups. In this study, MOTS-c administration improved physical capacity in young (2 months), middle-aged (12 months), and old (22 months) mice. Notably, exercise was shown to increase endogenous MOTS-c expression in human skeletal muscle, suggesting that MOTS-c may mediate some of the well-known benefits of physical activity (Reynolds et al., 2021). Furthermore, late-life-initiated intermittent MOTS-c treatment (3 times per week) improved physical capacity and healthspan in aged mice, suggesting potential applications in age-related physical decline research.

Obesity and Adipose Tissue Regulation

MOTS-c has demonstrated anti-obesity effects through multiple mechanisms. In high-fat diet models, MOTS-c treatment prevented diet-induced obesity, reduced body weight gain, and improved lipid profiles. Research indicates that MOTS-c regulates adipose homeostasis by promoting the browning of white adipose tissue and activating brown adipose tissue thermogenesis (Lu et al., 2019). These effects, combined with its AMPK-mediated enhancement of fatty acid oxidation, make MOTS-c a subject of active investigation in obesity research.

Bone Metabolism and Osteoporosis

Emerging research has revealed that MOTS-c plays a significant role in bone metabolism. Studies demonstrate that MOTS-c promotes osteoblast proliferation, differentiation, and mineralization while inhibiting osteoclast formation through the AMPK and TGF-β/SMAD signaling pathways (Qin et al., 2018; Hu & Chen, 2019). In ovariectomized rat models of osteoporosis, MOTS-c promoted osteogenic differentiation of bone mesenchymal stem cells, suggesting potential applications in postmenopausal osteoporosis research. A comprehensive review confirmed MOTS-c's role in promoting bone formation through type I collagen synthesis (Yi et al., 2023).

Aging and Healthspan

Given that endogenous MOTS-c levels decline with age, exogenous MOTS-c supplementation has been investigated as a potential intervention for age-related metabolic decline. Research demonstrates that MOTS-c can reverse age-dependent insulin resistance in skeletal muscle, improve physical capacity in aged animals, and enhance overall healthspan markers (Mohtashami et al., 2022). These properties make MOTS-c a promising candidate in longevity and anti-aging peptide research, alongside peptides such as Epithalon and NAD+.

Cardiovascular Protection

Recent studies have expanded MOTS-c research into cardiovascular health. In a mouse model of pressure-overload-induced heart failure, MOTS-c administration attenuated cardiac dysfunction and remodeling while reducing inflammatory responses and upregulating antioxidant capacity via AMPK activation (Wu et al., 2022). This emerging area of research suggests that MOTS-c's anti-inflammatory and antioxidant properties may extend to cardioprotective applications.

Published Research Studies

MOTS-c has been the subject of numerous peer-reviewed publications since its discovery. Below are key studies that have shaped the field:

1. Discovery of MOTS-c and Metabolic Regulation (2015)

Lee et al., 2015 — Published in Cell Metabolism, this seminal study identified MOTS-c as a novel mitochondrial-derived peptide encoded within the 12S rRNA gene. The researchers demonstrated that MOTS-c targets skeletal muscle, inhibits the folate cycle, activates AMPK, and prevents age-dependent and high-fat-diet-induced insulin resistance and obesity in mice. This paper established MOTS-c as a key player in metabolic homeostasis.

2. Nuclear Translocation Under Metabolic Stress (2018)

Kim et al., 2018 — Published in Cell Metabolism, this study revealed that MOTS-c translocates to the nucleus in an AMPK-dependent manner following metabolic stress. In the nucleus, MOTS-c regulates genes with antioxidant response elements (ARE) and interacts with NRF2 and other stress-responsive transcription factors. This was the first demonstration that a mitochondrial-encoded peptide can directly regulate nuclear gene expression.

3. Exercise-Induced MOTS-c and Aging (2021)

Reynolds et al., 2021 — Published in Nature Communications, this study showed that MOTS-c is exercise-induced, enhances physical performance across all age groups in mice, and that late-life MOTS-c treatment improves healthspan. The researchers also confirmed that exercise increases endogenous MOTS-c expression in human skeletal muscle.

4. MOTS-c Reduces Myostatin and Muscle Atrophy (2021)

Kumagai et al., 2021 — Published in the American Journal of Physiology - Endocrinology and Metabolism, this study demonstrated that MOTS-c reduces myostatin levels and prevents muscle atrophy signaling in diet-induced obese mice. Plasma MOTS-c levels were inversely correlated with myostatin levels in human subjects, and MOTS-c protected against palmitic acid-induced atrophy in myotubes via AKT phosphorylation.

5. MOTS-c in Bone Metabolism and Osteoporosis (2018–2023)

Multiple studies have investigated MOTS-c's role in bone health. Qin et al. (2018) demonstrated that MOTS-c promotes osteogenic differentiation of BMSCs via the TGF-β/Smad pathway. Hu & Chen (2019) confirmed that MOTS-c promotes type I collagen synthesis in osteoblasts through the same pathway. A 2023 review by Yi et al. comprehensively summarized MOTS-c's role in bone metabolism regulation.

Dosage Protocols in Research

Note: The following information summarizes dosages used in published research studies and is provided for reference purposes only. MOTS-c is sold strictly for research purposes.

Animal Study Dosages

In the original discovery study, Lee et al. (2015) administered MOTS-c to mice via intraperitoneal (IP) injection at a dose of 5 mg/kg/day for periods ranging from 7 to 14 days. This dosage was sufficient to prevent diet-induced obesity and insulin resistance. In the exercise and aging study, Reynolds et al. (2021) used 15 mg/kg IP injections administered three times per week for a late-life intervention protocol spanning multiple weeks. For the heart failure study, Wu et al. (2022) used subcutaneous administration via osmotic pump for sustained delivery.

In Vitro Study Concentrations

Cell culture studies have employed MOTS-c at concentrations ranging from 0.5 μM to 10 μM. Hu & Chen (2019) found that 0.5–1.0 μM MOTS-c treatment enhanced osteoblast cell viability and collagen synthesis. In myotube experiments, Kumagai et al. (2021) used 10 μM MOTS-c to prevent palmitic acid-induced atrophy in C2C12 cells.

Reconstitution

For research applications, MOTS-c lyophilized powder is typically reconstituted in sterile bacteriostatic water or sterile saline. For detailed guidance on peptide preparation, see our how to reconstitute peptides guide. The reconstituted solution should be used promptly or stored according to appropriate cold-chain protocols.

Storage and Handling

Proper storage of MOTS-c is essential to maintain peptide integrity and biological activity for research applications. As with all research peptides, following appropriate storage protocols ensures consistent experimental results.

Lyophilized (unreconstituted) MOTS-c:

• Store at -20°C or colder for long-term storage (recommended for maximum stability)
• Stable at room temperature during shipping for short periods
• Protect from light and moisture
• Shelf life: Up to 24 months when stored at -20°C in sealed, desiccated vials

Reconstituted MOTS-c:

• Store at 2–8°C (refrigerated) for short-term use (up to 2–4 weeks)
• For longer storage, aliquot and freeze at -20°C to avoid repeated freeze-thaw cycles
• Use sterile technique during reconstitution to prevent contamination
• Do not use if the solution appears cloudy or contains particulate matter

For comprehensive storage guidance, refer to our how to store research peptides guide. Given the relatively small size of MOTS-c (16 amino acids), it tends to be more stable than larger peptide molecules, but standard cold-chain practices should still be followed.

Safety Profile in Research

MOTS-c has demonstrated a favorable safety profile across numerous preclinical studies. As an endogenous peptide naturally produced in the mitochondria of human cells and detectable in circulating plasma, MOTS-c is not a foreign substance to the body, which may contribute to its tolerability in research settings.

In animal studies, MOTS-c administration at doses of 5–15 mg/kg via intraperitoneal injection or subcutaneous delivery did not produce significant adverse effects in mice across multiple study durations (Lee et al., 2015; Reynolds et al., 2021). In the late-life intervention study, aged mice receiving MOTS-c three times weekly showed improved physical capacity and healthspan markers without reported toxicity.

It is important to note that MOTS-c research is still in preclinical stages. No human clinical trials have been completed to fully characterize the safety profile, pharmacokinetics, or potential long-term effects of exogenous MOTS-c administration in humans. The molecular mechanisms of MOTS-c — particularly its effects on AMPK signaling, nuclear gene regulation, and metabolic homeostasis — are well documented in animal and cell culture models, but translation to human safety data awaits formal clinical investigation. Researchers should review the current literature and consult our research peptide safety guide for general best practices when handling peptides in laboratory environments.

Related Peptides

MOTS-c belongs to the broader family of mitochondrial-derived peptides (MDPs) and metabolic regulatory peptides. Researchers studying MOTS-c may also be interested in the following related compounds:

• NAD+ 500mg — Nicotinamide adenine dinucleotide, a critical coenzyme in mitochondrial energy metabolism. Like MOTS-c, NAD+ levels decline with age and supplementation is being researched for its metabolic and anti-aging potential. Learn more in our NAD+ research guide.
• Epithalon 50mg — A tetrapeptide studied for its effects on telomerase activation and anti-aging properties. Like MOTS-c, Epithalon targets age-related biological decline. See our Epithalon anti-aging research guide.
• AOD-9604 5mg — A modified fragment of human growth hormone researched for fat metabolism and weight management, complementing MOTS-c's anti-obesity research profile. Read our AOD-9604 research guide.
• IPP-1 SM 10mg — A GLP-1 receptor agonist widely researched for metabolic regulation and weight management. Explore our GLP-1 receptor agonist guide to compare metabolic peptide mechanisms.

For a comprehensive overview of peptide combinations in metabolic and aging research, visit our guide on best peptide stack combinations.

Frequently Asked Questions

What is MOTS-c used for in research?

MOTS-c is primarily used in research investigating metabolic regulation, insulin sensitivity, exercise physiology, obesity, aging, bone metabolism, and cardiovascular health. As a mitochondrial-derived peptide that activates the AMPK pathway and can translocate to the nucleus to regulate gene expression, MOTS-c provides researchers with a unique tool to study mitochondrial-nuclear communication and metabolic homeostasis.

How does MOTS-c differ from other mitochondrial-derived peptides like Humanin?

While both MOTS-c and Humanin are encoded within the mitochondrial genome, they have distinct structures, mechanisms, and biological activities. MOTS-c is a 16-amino-acid peptide encoded in the 12S rRNA gene that primarily targets skeletal muscle metabolism through the folate-AICAR-AMPK pathway. Humanin is a 24-amino-acid peptide encoded in the 16S rRNA gene that primarily exhibits cytoprotective and anti-apoptotic effects. MOTS-c is unique in its ability to translocate to the nucleus and directly regulate nuclear gene expression in response to metabolic stress.

What is the significance of MOTS-c as an exercise mimetic?

Research has shown that exercise induces endogenous MOTS-c expression in human skeletal muscle, and exogenous MOTS-c administration enhances physical performance in mice of all ages. This suggests MOTS-c may partially mediate the metabolic benefits of exercise, making it a subject of intense interest in exercise physiology and aging research (Reynolds et al., 2021).

Does MOTS-c affect bone density in research models?

Yes. Multiple studies have demonstrated that MOTS-c promotes osteoblast differentiation, mineralization, and type I collagen synthesis through the TGF-β/SMAD pathway. In animal models of osteoporosis, MOTS-c treatment improved osteogenic differentiation of bone marrow mesenchymal stem cells, suggesting potential relevance to bone health research (Qin et al., 2018; Yi et al., 2023).

How should MOTS-c be stored for research use?

Lyophilized MOTS-c should be stored at -20°C or colder for long-term stability. Once reconstituted, it should be stored at 2–8°C for short-term use (up to 2–4 weeks) or aliquoted and frozen at -20°C for longer storage. Avoid repeated freeze-thaw cycles. See our peptide storage guide for detailed instructions.

What is the purity of Iron Peak Peptides MOTS-c?

Iron Peak Peptides provides MOTS-c with a minimum purity of ≥99%, verified by third-party HPLC and mass spectrometry analysis. A quality assurance documentation is available for every batch, ensuring researchers receive a reliable, high-quality product for their investigations.

Can MOTS-c be combined with other peptides in research?

Researchers have explored MOTS-c in the context of broader metabolic and anti-aging research protocols. While specific combination studies are limited, MOTS-c's unique AMPK-mediated mechanism of action makes it mechanistically compatible with peptides targeting complementary pathways, such as NAD+ for mitochondrial support or Epithalon for telomere-related aging research. Always review published literature before designing combination protocols.

Why Buy MOTS-c from Iron Peak Peptides?

Iron Peak Peptides is committed to providing researchers with the highest-quality MOTS-c peptide available. Every batch of our MOTS-c 10mg is manufactured under strict quality control standards and verified through rigorous third-party testing protocols.

Our quality assurance includes:

• ≥99% Purity Guarantee — Verified by independent HPLC (High-Performance Liquid Chromatography) analysis
• Mass Spectrometry Confirmation — Molecular identity confirmed via MS to ensure accurate peptide sequence (MRWQEMGYIFYPRKLR)
• quality assurance documentation — Provided with every order, documenting purity, identity, and quality metrics
• Third-Party Testing — All products tested by independent laboratories to ensure unbiased results
• Proper Lyophilization and Packaging — Each vial is sealed under controlled conditions to ensure maximum stability and shelf life

As one of the most exciting mitochondrial-derived peptides in current research, MOTS-c requires a reliable, high-purity source for consistent experimental results. Iron Peak Peptides delivers research-grade MOTS-c backed by transparent quality documentation, fast shipping, and dedicated customer support for the research community. For more information about our complete line of MOTS-c research resources, explore our comprehensive guide on this revolutionary mitochondrial peptide.

References

1. Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism. 2015;21(3):443-454.
2. Lee C, Kim KH, Cohen P. MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radical Biology and Medicine. 2016;100:182-187.
3. 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 Metabolism. 2018;28(3):516-524.e7.
4. Reynolds JC, Lai RW, Woodhead JST, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications. 2021;12(1):470.
5. Kumagai H, Coelho AR, Wan J, et al. MOTS-c reduces myostatin and muscle atrophy signaling. American Journal of Physiology - Endocrinology and Metabolism. 2021;320(4):E680-E690.
6. Qin Q, Delrio S, Wan J, et al. MOTS-c improves osteoporosis by promoting osteogenic differentiation of bone marrow mesenchymal stem cells via TGF-β/Smad pathway. European Review for Medical and Pharmacological Sciences. 2018;22(21):7156-7163.
7. Hu BT, Chen WZ. MOTS-c improves osteoporosis by promoting the synthesis of type I collagen in osteoblasts via TGF-β/SMAD signaling pathway. European Review for Medical and Pharmacological Sciences. 2019;23(8):3567-3573.
8. Lu H, Wei M, Zhai Y, et al. MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction. Journal of Molecular Medicine. 2019;97(4):473-485.
9. Wu N, Shen C, Wang J, Chen X, Zhong P. Mitochondrial derived peptide MOTS-c prevents the development of heart failure. Journal of Cellular and Molecular Medicine. 2022;26(20):5369-5380.
10. Mohtashami Z, Singh MK, Salimiaghdam N, Ozgul M, Kenney MC. MOTS-c, the most recent mitochondrial derived peptide in human aging and age-related diseases. International Journal of Molecular Sciences. 2022;23(19):11991.
11. Wan W, Zhang L, Lin Y, et al. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. Journal of Translational Medicine. 2023;21(1):36.
12. Yi X, et al. Role of MOTS-c in the regulation of bone metabolism. Frontiers in Cell and Developmental Biology. 2023;11:1132025.