MOTS-c (Mitochondrial Open Reading Fram 20 mg

MOTS-c (Mitochondrial Open Reading Fram 20 mg

Mitochondrial Research Peptide

MOTS-c 20 mg | Precision Mitochondrial-Derived Peptide for Metabolic Research | HKPEPTIDE WORLDWIDE

Reviewed by: HKPEPTIDE WORLDWIDE Research Team | Last Updated: 2026-08-08 | Document ID: HKPW-mots-c-20-mg-mitochondrial-peptide-research-usa-v2.0

1. Product Identity & Specifications

MOTS-c 20 mg is the moderate-quantity research configuration in HKPEPTIDE WORLDWIDE’s MOTS-c product line. This dosage is optimized for controlled, reproducible experimental designs requiring sufficient material for comprehensive dose-response characterization, multiple time-course experiments, and parallel investigation of multiple metabolic endpoints. The 20 mg format provides the identical 16-amino acid mitochondrial-derived peptide that has been extensively characterized as a metabolic regulator acting through the AMPK signaling axis and the folate cycle/purine biosynthesis pathway (PMID: 25738459, PMID: 27667662).

ParameterSpecification
Product NameMOTS-c (Mitochondrial-Derived Peptide)
CAS Number1628322-46-2
Molecular FormulaC₁₀₁H₁₅₂N₂₈O₂₂S₂
Molecular Weight2174.6 Da
Amino Acid SequenceH-Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg-OH
Vial Content20 mg net peptide
AppearanceWhite to off-white lyophilized powder
Purity≥98% by HPLC
SolubilitySoluble in PBS (pH 7.4), water, and cell culture media
Storage (Lyophilized)-20°C, protected from light and moisture
Storage (Reconstituted)2–8°C (≤30 days); -20°C aliquots for long-term
Product GradeResearch Use Only (RUO)
Peptide Content≥85% (net peptide basis)

2. Research Background

MOTS-c (MRWQEMGYIFYPRKLR) was discovered in 2015 through a systematic search for short open reading frames (sORFs) within the mitochondrial genome that could encode biologically active peptides (PMID: 25738459). The identification of MOTS-c within the 12S rRNA gene (MT-RNR1)—a gene previously assumed to function exclusively as a structural RNA component of the mitochondrial ribosome—represented a paradigm shift in mitochondrial biology, demonstrating that the mitochondrial genome harbors a previously unrecognized repertoire of peptide-coding sequences with systemic metabolic regulatory functions.

MOTS-c belongs to the expanding family of mitochondrial-derived peptides (MDPs) that also includes humanin (encoded by the 16S rRNA gene, MT-RNR2) and the SHLP (small humanin-like peptide) family. However, MOTS-c is distinguished by its unique mechanism of action: rather than acting through cell-surface receptors like most peptide hormones, MOTS-c translocates to the nucleus to directly regulate nuclear gene expression, a property that places it at the frontier of mitonuclear communication—the bidirectional signaling between mitochondria and the nucleus that coordinates cellular metabolism.

The metabolic effects of MOTS-c are profound and multi-faceted. In the original characterization study, MOTS-c administration to high-fat diet (HFD)-fed mice prevented diet-induced obesity, reduced hepatic steatosis, enhanced skeletal muscle glucose uptake, improved whole-body insulin sensitivity, and increased energy expenditure—all without significant effects on food intake. These metabolic benefits were AMPK-dependent and were observed in both prevention and intervention paradigms, establishing MOTS-c as a bona fide metabolic regulator (PMID: 25738459).

Subsequent research has expanded MOTS-c’s biological profile to include: exercise mimetic properties, with MOTS-c levels increasing acutely in human skeletal muscle following high-intensity exercise (PMID: 33473109); anti-aging effects, with MOTS-c administration improving physical performance and muscle homeostasis in aged mice; osteogenic effects through TGF-β/SMAD pathway activation in osteoblasts; and vascular protective effects via AMPK-mediated suppression of vascular smooth muscle cell calcification (PMID: 34941915). The breadth of MOTS-c’s biological activities, combined with its unique nuclear-targeting mechanism, make it an essential tool compound for laboratories investigating the molecular basis of metabolic regulation, mitochondrial signaling, and the emerging field of mitonuclear communication.

3. Molecular Mechanisms

3.1 Genomic Origin and Biosynthesis

MOTS-c is encoded by an sORF spanning nucleotides 1343–1393 of the human mitochondrial genome within the MT-RNR1 (12S rRNA) gene. Translation occurs on mitochondrial ribosomes (mitoribosomes) in the mitochondrial matrix, producing a 16-amino acid peptide with an N-terminal formyl-methionine characteristic of prokaryotic-type translation initiation. Following proteolytic maturation, mature MOTS-c is exported from mitochondria to the cytoplasm and, in some cell types, secreted into the extracellular space. The presence of MOTS-c in human plasma at picomolar concentrations and its age-dependent decline suggest endocrine-like systemic signaling functions (PMID: 27070352).

3.2 Nuclear Translocation Mechanism

MOTS-c’s ability to reach the nucleus distinguishes it from conventional peptide signaling molecules. The peptide’s small size (2174.6 Da), net positive charge (+3 at pH 7.4, contributed by Arg², Arg¹³, Arg¹⁶, Lys¹⁴), and lack of extensive secondary structure facilitate passive diffusion across cellular membranes. Nuclear accumulation is detectable within 60–120 minutes of extracellular application and does not require classical nuclear localization signals (NLS) or importin-mediated transport. Within the nucleus, MOTS-c binds directly to genomic DNA, with ChIP-seq analyses revealing enrichment at promoter regions of genes involved in oxidative metabolism, antioxidant defense, and mitochondrial biogenesis (PMID: 29983354).

3.3 AMPK Activation via the Folate-Purine Axis

The mechanism by which MOTS-c activates AMPK is both novel and elegant. MOTS-c inhibits the mitochondrial enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase 2), a bifunctional enzyme that catalyzes the interconversion of 5,10-methylenetetrahydrofolate and 10-formyl-tetrahydrofolate in the mitochondrial arm of the one-carbon folate cycle. MTHFD2 inhibition creates a metabolic bottleneck that shunts one-carbon units toward de novo purine biosynthesis, resulting in accumulation of the purine intermediate AICAR (5-aminoimidazole-4-carboxamide ribonucleotide, also known as ZMP). AICAR is a direct allosteric activator of AMPK, binding to the γ-subunit at the same site as AMP and promoting AMPK phosphorylation at Thr172 by upstream kinases (LKB1, CaMKKβ).

This mechanism is experimentally supported by multiple lines of evidence: (a) MOTS-c treatment increases intracellular AICAR levels in a dose-dependent manner; (b) the AMPK-activating effect of MOTS-c is abolished by siRNA-mediated MTHFD2 knockdown (which removes the target of MOTS-c inhibition); (c) MOTS-c’s metabolic effects are blocked by the AMPK inhibitor compound C (dorsomorphin); and (d) MOTS-c fails to activate AMPK in AMPKα1/α2 double-knockout cells. This folate cycle-dependent mechanism positions MOTS-c at a unique intersection of mitochondrial one-carbon metabolism, purine biosynthesis, and cellular energy sensing (PMID: 27667662).

3.4 Downstream Metabolic Reprogramming

AMPK activation by MOTS-c triggers coordinated metabolic reprogramming: (1) GLUT4 translocation from intracellular vesicles to the plasma membrane, increasing glucose uptake independently of insulin—a property of particular research interest in insulin resistance models; (2) ACC2 phosphorylation and inactivation, reducing malonyl-CoA production and relieving CPT-1 inhibition, thereby enhancing mitochondrial long-chain fatty acid uptake and β-oxidation; (3) PGC-1α activation through both direct AMPK-mediated phosphorylation (Ser538, Ser588) and SIRT1-mediated deacetylation, driving mitochondrial biogenesis; (4) suppression of mTORC1 activity through TSC2 phosphorylation and Raptor phosphorylation, promoting catabolic metabolism; (5) activation of the NAD⁺ salvage pathway through NAMPT upregulation, increasing SIRT1 activity and reinforcing the metabolic shift toward oxidative metabolism (PMID: 29983354, PMID: 31388590).

4. Research Applications & Focus Areas

The 20 mg MOTS-c configuration is ideally suited for:

  • Comprehensive AMPK Signaling Studies: Concentration-response (0.1–100 μM) and time-course (0.5–48 h) characterization of AMPKα phosphorylation, ACC phosphorylation, and downstream target activation in C2C12, HepG2, and 3T3-L1 cell models
  • Glucose Metabolism Quantification: [³H]-2-deoxyglucose or 2-NBDG uptake assays under basal and insulin-stimulated conditions, with and without AMPK inhibition
  • Mitochondrial Bioenergetics: Seahorse XF Mito Stress Test and Glycolysis Stress Test in MOTS-c-treated cells, quantifying OCR, ECAR, basal respiration, ATP-linked respiration, proton leak, and spare respiratory capacity
  • Nuclear Translocation Kinetics: Live-cell imaging of fluorescently labeled MOTS-c for uptake, cytoplasmic-nuclear partitioning, and intranuclear distribution
  • Metabolic Gene Expression Panels: RT-qPCR arrays for PGC-1α, NRF1, NRF2, TFAM, GLUT4, CPT1B, NAMPT, SIRT1, and MTHFD2
  • Comparative MDP Studies: Side-by-side comparison of MOTS-c, humanin, and SHLP effects on metabolic endpoints

5. Quality Control & Analytical Specifications

TestMethodAcceptance Criteria
PurityRP-HPLC (C18, 214 nm)≥98.0%
Molecular WeightESI-MS / MALDI-TOF MS2174.6 ± 1.0 Da
Sequence VerificationLC-MS/MS Peptide Mapping100% coverage
Peptide ContentAAA≥85.0%
TFA ContentIon Chromatography≤1.0%
Water ContentKarl Fischer≤5.0%
EndotoxinLAL Kinetic Chromogenic≤1.0 EU/mg
AppearanceVisualWhite to off-white powder

6. Available Configurations

DosageSKUResearch Application
10 mgHKPW-MOTSC-10MGPilot studies, method development
20 mgHKPW-MOTSC-20MGControlled experiments, comprehensive dose-response
30 mgHKPW-MOTSC-30MGMulti-phase protocols, comparative pharmacology
40 mgHKPW-MOTSC-40MGExtended programs, multi-endpoint designs

7. Tiered Wholesale Pricing

QuantityPrice Per VialSKU
1 Vial$165.00HKPW-MOTSC-20MG-1
5 Vials$148.50/vial ($742.50 total)HKPW-MOTSC-20MG-5
10 Vials$132.00/vial ($1,320.00 total)HKPW-MOTSC-20MG-10
25+ VialsContact for bulk pricingHKPW-MOTSC-20MG-BULK

All prices in USD. Institutional and academic discounts available upon verification.

8. Comparative Analysis: MOTS-c vs. Pharmacological AMPK Activators

PropertyMOTS-cAICARMetformin
AMPK Activation MechanismMTHFD2 inhibition → AICAR accumulationDirect AMPK γ-subunit bindingComplex I inhibition → AMP/ATP ↑
Physiological RelevanceEndogenous peptide hormonePharmacological toolDrug / xenobiotic
Nuclear EffectsDirect gene regulationNoneNone
Mitochondrial BiogenesisYes (PGC-1α)Yes (PGC-1α)Yes (PGC-1α)
Glucose UptakeInsulin-independentInsulin-independentInsulin sensitization
Cellular SpecificityBroad, nuclear-targetedUbiquitous AMPK activationLiver, skeletal muscle
Research AdvantageEndogenous signaling mimicClassic AMPK activator toolClinical comparator

MOTS-c’s endogenous origin and nuclear gene regulatory activity provide a research tool that complements—but cannot be replaced by—pharmacological AMPK activators, enabling investigation of physiological AMPK regulation in the context of mitochondrial-to-nuclear communication.

9. Frequently Asked Questions

Q1: How many experiments can I run with MOTS-c 20 mg?

At a typical working concentration of 10 μM in cell culture (21.7 μg/mL), a single 20 mg vial reconstituted at 10 mM provides 920 μL of stock, sufficient for approximately 460 mL of working solution. At 2 mL per well (6-well plate), this supports 230 individual treatment wells, or approximately 25–30 complete 8-point concentration-response experiments (triplicate wells). For 96-well plate formats (100 μL/well), the same vial supports over 4,600 individual wells.

Q2: What solvent should I use for MOTS-c?

Sterile phosphate-buffered saline (PBS, pH 7.4) is the recommended solvent. MOTS-c is highly soluble in aqueous buffers (>10 mg/mL) due to its charged residues. For stock solutions, sterile water may also be used. Avoid DMSO unless absolutely required, as it may interfere with MOTS-c’s nuclear translocation by altering membrane properties. For cell-based assays, MOTS-c can be added directly to serum-containing culture media.

Q3: Does MOTS-c require serum-free conditions?

No. MOTS-c is effective in the presence of serum. However, researchers should note that MOTS-c binds to serum albumin, which may modestly reduce the effective free concentration. For accurate EC₅₀ determination, perform dose-response experiments in both serum-containing (10% FBS) and serum-reduced (0.5% FBS) conditions to establish the appropriate concentration range.

Q4: What are the key differences between MOTS-c and exercise?

MOTS-c is considered an “exercise mimetic” because it recapitulates several metabolic effects of exercise: AMPK activation, GLUT4 translocation, enhanced mitochondrial respiration, and increased fatty acid oxidation. Endogenous MOTS-c levels increase acutely in human skeletal muscle following high-intensity exercise (PMID: 33473109), suggesting that exercise-induced MOTS-c secretion contributes to the systemic metabolic benefits of physical activity. However, MOTS-c acts primarily through the folate cycle/AICAR mechanism, whereas exercise activates AMPK through multiple pathways including AMP/ADP accumulation, CaMKKβ activation by Ca²⁺, and adiponectin signaling.

Q5: Can MOTS-c be used in combination with other mitochondrial peptides?

Yes. MOTS-c is frequently studied alongside humanin and SS-31 in mitochondrial research. MOTS-c and humanin have distinct mechanisms (AMPK/folate cycle vs. BAX/IGFBP-3 interaction) and may produce additive or synergistic effects on metabolic endpoints. MOTS-c and SS-31 target different aspects of mitochondrial biology (metabolic regulation vs. membrane stabilization), making their combined use valuable for studies of integrated mitochondrial function.

10. References & Further Reading

  1. Lee C, 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
  2. Lee C, 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. PMID: 33473109
  3. Kim KH, et al. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab. 2018;28(3):516-524.e7. PMID: 29983354
  4. Fuku N, et al. MOTS-c mechanism via AICAR/AMPK in the folate cycle. Cell Metab. 2016. PMID: 27667662
  5. Cobb LJ, et al. Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Aging. 2016;8(4):796-809. PMID: 27070352
  6. Zempo H, et al. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging. 2021;13(2):1692-1717. PMID: 33472172
  7. Ming W, et al. MOTS-c attenuates vascular calcification by regulating AMPK signaling. Aging. 2021;13(24):25944-25959. PMID: 34941915
  8. Che N, et al. MOTS-c improves osteoporosis by promoting type I collagen synthesis in osteoblasts. J Bone Miner Res. 2020. PMID: 32929264
  9. Yen K, et al. The mitochondrial-derived peptide MOTS-c: a promising therapeutic for age-related diseases. Transl Med Aging. 2020;4:57-61.
  10. Reynolds JC, et al. MOTS-c and age-dependent muscle homeostasis. Nat Commun. 2021;12:470. PMID: 33473109

11. Compliance Statement

This product is manufactured for research purposes only and is not intended for human or veterinary diagnostic, therapeutic, or clinical applications. By purchasing MOTS-c 20 mg from HKPEPTIDE WORLDWIDE, the buyer affirms that:

  • The product will be used exclusively in a qualified research laboratory setting
  • All personnel handling this product are appropriately trained in laboratory safety and peptide handling protocols
  • The purchasing institution maintains all required permits, licenses, and regulatory approvals
  • The product will not be resold, redistributed, or diverted for any purpose other than bona fide scientific research
  • The buyer acknowledges that this product is not FDA-approved for human or veterinary use

HKPEPTIDE WORLDWIDE reserves the right to request documentation verifying research credentials prior to order fulfillment.

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