MOTS-c (Mitochondrial Open Reading Frame of the Twelve S rRNA type-c) is a 16-amino-acid mitochondrial-derived peptide (MDP) encoded within the mitochondrial 12S ribosomal RNA gene. BioSim Peptides offers MOTS-c 40mg as a lyophilized research-grade preparation supplied strictly for in-vitro laboratory research use only.
The following overview consolidates the chemistry, signaling, and published research on the MOTS-c mitochondrial peptide to support investigators working in metabolic, exercise, and mitochondrial-biology model systems.
What is MOTS-c?
MOTS-c is a short bioactive peptide with the sequence MRWQEMGYIFYPRKLR, translated from a small open reading frame embedded in the mitochondrial 12S rRNA locus. Its molecular formula is approximately C100H149N29O22S2 and its monoisotopic mass is roughly 2,174.1 Da. Because it is encoded in mitochondrial DNA rather than the nuclear genome, MOTS-c belongs to a distinctive class of regulators sometimes described as the “mitochondrial peptidome”.
The peptide was first characterized by Lee, Cohen, and colleagues in 2015, who showed that MOTS-c is detectable in plasma and multiple tissues and acts as a regulator of insulin sensitivity and metabolic homeostasis (Lee et al., 2015). Subsequent work has positioned MOTS-c alongside humanin and the SHLP family as mitochondrial-derived peptides that participate in inter-organelle and inter-tissue signaling. Investigators studying exercise physiology, aging, and skeletal-muscle metabolism use MOTS-c as a probe of mitochondrial-to-nuclear retrograde communication.
Mechanism of Action in Research Models
In cultured cells and rodent tissues, MOTS-c activates AMP-activated protein kinase (AMPK) and increases the cellular AICAR-like de novo purine biosynthesis intermediate 5-aminoimidazole-4-carboxamide ribonucleotide. Through AMPK activation, MOTS-c enhances glucose uptake in skeletal muscle and shifts substrate utilization toward glycolytic flux while reducing methionine–folate-cycle intermediates (Lee et al., 2015). Downstream of AMPK, increased GLUT4 trafficking and improved insulin signaling have been described in MOTS-c–treated myocytes (Kim et al., 2019).
More recent investigations indicate that MOTS-c can translocate to the nucleus under metabolic stress, where it associates with stress-responsive transcription factors including NRF2 and modulates expression of antioxidant and metabolic genes. In skeletal muscle, MOTS-c has been reported to suppress myostatin signaling and attenuate atrophy-associated transcriptional programs (Kumagai et al., 2021). Collectively, these effects place MOTS-c at the intersection of energy sensing, mitochondrial quality control, and tissue-level metabolic adaptation.
Key Areas of Scientific Research
Insulin Sensitivity and Glucose Homeostasis
The seminal MOTS-c study demonstrated that exogenous MOTS-c improves glucose tolerance and reduces diet-induced obesity in murine models, with AMPK-dependent enhancement of glucose disposal in skeletal muscle (Lee et al., 2015). Follow-up work has extended these observations to gestational and pregnancy-associated insulin resistance models (Yin et al., 2022) and to clinical association studies linking circulating MOTS-c with whole-body insulin sensitivity (Cataldo et al., 2018).
Skeletal Muscle Biology
Researchers have examined MOTS-c as a counter-regulator of muscle wasting. Kumagai and colleagues showed that MOTS-c administration in rodents reduces myostatin expression and downstream Smad signaling, producing measurable changes in atrophy-related transcripts in skeletal muscle (Kumagai et al., 2021). These findings are of interest for sarcopenia and disuse models.
Exercise and Mitohormesis
Plasma MOTS-c rises in response to acute exercise in several preclinical paradigms, supporting the hypothesis that the peptide participates in exercise-induced adaptations and mitohormetic signaling. The mitochondrial peptide is being studied as a candidate endogenous “exercise mimetic” in cell culture and animal models (Kim et al., 2019).
Aging and Metabolic Disease Models
Circulating MOTS-c levels decline with age in some cohorts, and the peptide has been examined in models of obesity, fatty liver, and age-related metabolic dysfunction. Cross-sectional human investigation found that plasma MOTS-c correlated with insulin sensitivity in lean but not obese subjects, suggesting context-dependent regulation (Cataldo et al., 2018).
Published Research Highlights
- Lee, Zhang, and colleagues identified MOTS-c as a mitochondrial-derived peptide that promotes metabolic homeostasis, activates AMPK, and reduces diet-induced obesity and insulin resistance in mice (Lee et al., 2015, Cell Metabolism).
- Kumagai and coauthors demonstrated that MOTS-c reduces myostatin and muscle-atrophy signaling, supporting a role in skeletal muscle maintenance (Kumagai et al., 2021, American Journal of Physiology – Endocrinology and Metabolism).
- Yin and colleagues reported that MOTS-c relieves hyperglycemia and insulin resistance in a gestational diabetes mellitus model (Yin et al., 2022, Pharmacological Research).
- Cataldo and colleagues observed that plasma MOTS-c levels associate with insulin sensitivity in lean but not obese individuals, highlighting metabolic context (Cataldo et al., 2018, Journal of Investigative Medicine).
- Kim reviewed MOTS-c as an “equal opportunity insulin sensitizer”, summarizing tissue-level effects and AMPK-centered mechanisms (Kim et al., 2019, Journal of Molecular Medicine).
Cardiovascular and Endothelial Research
Beyond skeletal muscle and adipose tissue, MOTS-c has been investigated in endothelial and cardiomyocyte models where it influences nitric oxide signaling, oxidative stress responses, and ischemia-related transcriptional programs. These studies place MOTS-c within a broader mitochondrial-peptide framework that includes humanin and the small humanin-like peptides (SHLPs), several of which exhibit overlapping cytoprotective signatures.
Bone and Inflammatory Models
Preclinical investigation has extended to osteogenic differentiation and inflammatory bone-loss paradigms, with MOTS-c reported to modulate osteoclast and osteoblast activity in cell-culture systems. Investigators using MOTS-c as a tool peptide can interrogate the interface between mitochondrial fitness and inflammatory cytokine signaling, a question of growing interest in immunometabolism.
Comparative Mitochondrial Peptidome Biology
MOTS-c is one member of an expanding family of mitochondrial-derived peptides that also includes humanin (a 24-residue peptide from the 16S rRNA region) and SHLP1–6. Comparative studies use MOTS-c alongside humanin to dissect overlapping and divergent contributions to apoptosis, metabolic regulation, and stress signaling, often using AMPK activation and Akt phosphorylation as shared readouts in cultured myocytes and neurons.
Polymorphisms and Population Genetics
A coding variant within the MOTS-c locus has been associated with metabolic phenotypes in some East Asian cohorts, motivating mechanistic studies in cell lines reconstituted with wild-type versus variant peptide. Such work illustrates the value of MOTS-c as both a chemical biology probe and an entry point into mitochondrial genetics, where nuclear-mitochondrial communication is increasingly recognized as a determinant of metabolic resilience.
Stability, Storage, and Handling in Laboratory Settings
Lyophilized MOTS-c is supplied as a sterile white powder and should be stored desiccated at -20°C protected from light. As a relatively short peptide containing methionine and tryptophan residues, MOTS-c is sensitive to oxidation, and exposure to oxygen, moisture, and prolonged room-temperature storage should be minimized.
Reconstitution in the laboratory is typically performed with sterile bacteriostatic water or 0.1% acetic acid for solubilization, with gentle inversion. Reconstituted solutions are commonly held at 2–8°C for short-term experiments and aliquoted at -20°C for longer storage to avoid freeze–thaw cycles, which can compromise integrity of the peptide.
Product Specifications
- Sequence: MRWQEMGYIFYPRKLR (16 amino acids)
- Molecular formula: C100H149N29O22S2
- Molecular weight: ~2,174.6 Da
- Origin: mitochondrial 12S rRNA-encoded peptide (MDP family)
- Purity: ≥98% by HPLC
- Presentation: lyophilized white powder, 40 mg per vial
- Mass spectrometry confirmation included
- Certificate of Analysis: available on request
- Shipping: USA-based, tracked dispatch
Why Researchers Choose BioSim Peptides
BioSim Peptides supplies investigators across the United States with reference-grade research compounds suitable for demanding in-vitro and preclinical model work. Every batch produced under our supply program is independently tested by HPLC for chromatographic purity and confirmed by mass spectrometry for accurate molecular identity, with a Certificate of Analysis available on request for each lot.
Researchers working with our material benefit from a guaranteed minimum purity of 98%, lyophilized presentation in tamper-evident vials, domestic USA shipping with tracked carriers, and responsive technical support for handling, reconstitution, and storage questions. Our quality program is designed to deliver the lot-to-lot consistency that reproducible laboratory science requires.
Historical Context and Discovery
The discovery of MOTS-c emerged from a broader recognition that the mitochondrial genome encodes more than just the canonical 13 electron-transport-chain subunits, two rRNAs, and 22 tRNAs traditionally catalogued. Computational searches for small open reading frames embedded within mitochondrial rRNA genes identified candidate peptide-coding regions, and biochemical confirmation established MOTS-c as a translated product detectable in cells, tissues, and circulation (Lee et al., 2015). This finding expanded the conceptual framework of mitochondrial output to include bioactive peptides that signal to the nucleus and to distant tissues, a paradigm now broadly referred to as the mitochondrial peptidome or mitokines.
Subsequent years have seen MOTS-c integrated into the broader narrative of inter-organelle communication, where mitochondria are understood not merely as cellular powerhouses but as active participants in transcriptional control and systemic metabolic signaling. The peptide is encoded by a sequence whose nuclear translation has also been demonstrated, raising interesting questions about co-existence of mitochondrial and cytoplasmic translation routes for the same primary structure.
Assay Considerations and In-Vitro Workflow Notes
In cultured myocytes and hepatocytes, MOTS-c activity is commonly evaluated through AMPK phosphorylation at Thr172, ACC phosphorylation at Ser79, glucose uptake assays using 2-deoxyglucose or fluorescent analogs, and quantitative PCR of metabolic target genes. These readouts allow investigators to confirm peptide activity, validate lot consistency, and benchmark new MOTS-c batches against established preparations.
Because MOTS-c contains methionine and tryptophan residues that are susceptible to oxidation, investigators are advised to confirm peptide integrity by mass spectrometry on receipt and to monitor for the +16 Da oxidized methionine adduct in long-term storage conditions. Working dilutions are typically prepared fresh in serum-containing or serum-free media depending on the experimental design, with care taken to avoid surface adsorption to plasticware at low nanomolar concentrations.
For in-vivo preclinical paradigms reported in the literature, MOTS-c is often delivered via intraperitoneal injection in rodents at investigator-determined regimens, and plasma MOTS-c is measured using validated ELISA assays. Investigators planning such studies should consult primary literature for current best practices and verify that any assays used can distinguish synthetic from endogenous MOTS-c reliably.
Related Research Compounds
MOTS-c is one of several mitochondrial-derived peptides under active investigation. Humanin, a 24-residue peptide encoded within the 16S mitochondrial rRNA region, exhibits cytoprotective and metabolic activity and is frequently studied alongside MOTS-c. The SHLP1–6 family expands the mitochondrial peptidome further. Comparative studies of these peptides illuminate the broader logic of mitochondrial-to-nuclear retrograde signaling and its role in metabolic homeostasis.
References
- Lee C, Zhang J, Yen K, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443-454. PMID: 25738459.
- Kumagai H, Coelho AR, Wan J, et al. MOTS-c reduces myostatin and muscle atrophy signaling. Am J Physiol Endocrinol Metab. 2021;320(4):E680-E690. PMID: 33554779.
- Yin Y, Pan Y, He J, et al. The mitochondrial-derived peptide MOTS-c relieves hyperglycemia and insulin resistance in gestational diabetes mellitus. Pharmacol Res. 2022;175:105987. PMID: 34798268.
- Cataldo LR, Fernández-Verdejo R, Santos JL, Galgani JE. Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. J Investig Med. 2018;66(6):1019-1022. PMID: 29593067.
- Kim SJ, Xiao J, Wan J, Cohen P, Yen K. Mitochondrially derived peptides as novel regulators of metabolism. J Mol Med (Berl). 2019;97(4):441-450. PMID: 30788534.
- Merry TL, Chan A, Woodhead JST, et al. Mitochondrial-derived peptides in energy metabolism. Am J Physiol Endocrinol Metab. 2020;319(4):E659-E666. PMID: 32830549.
This peptide is supplied by BioSim Peptides for in-vitro laboratory research use only. It is not a drug, supplement, cosmetic, or food product and is not intended for human or veterinary use, consumption, diagnosis, treatment, cure, or prevention of any disease. All research must comply with applicable institutional and regulatory guidelines.
Frequently Asked Questions about MOTS-c
What is MOTS-c?
MOTS-c is a research peptide supplied by BioSim Peptides for in-vitro and laboratory use only. Each vial is lyophilized, lab-tested, and accompanied by a Certificate of Analysis (COA) verifying identity and purity above 98% by HPLC.
Is the MOTS-c from BioSim Peptides third-party tested?
Yes. Every lot of MOTS-c 40mg is independently tested by HPLC and mass spectrometry. The COA for the current batch is available on request and packaged with every order.
How should MOTS-c be stored?
Lyophilized MOTS-c should be stored at -20°C for long-term stability. After reconstitution with bacteriostatic water it is typically stored at 2-8°C and used within the timeframe described in the published literature for the peptide.
How fast does BioSim Peptides ship?
Orders placed before 2 PM ET ship same business day from our USA facility via tracked carriers. Most domestic orders arrive in 2-4 business days.
Is MOTS-c approved for human use?
No. MOTS-c is supplied for in-vitro laboratory research only. It is not a drug, dietary supplement, cosmetic, or food, and is not intended for diagnosis, treatment, cure, or prevention of any disease in humans or animals.
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