Description
Summary Abstract
MOTS-C / 5-Amino-1MQ Blend (P-066; MOTS-C 10 MG + 5-Amino-1MQ 10 MG; 20 MG total lyophilized vial) combines two mechanistically complementary metabolic regulators that target non-overlapping nodes of cellular energy homeostasis. MOTS-C (Mitochondrial ORF of the Twelve-S rRNA type-c; CAS 1627580-64-6; MW 2,174.64 g/mol; 16 AA; MRWQEMGYIFYPRKLR) is a mitochondrial-derived peptide (MDP) encoded within the mitochondrial 12S rRNA gene (MT-RNR1) that activates AMP-Activated Protein Kinase (AMPK) by intercepting the folate and one-carbon cycle, with skeletal muscle as its primary target organ; under metabolic stress it translocates to the nucleus to modulate adaptive gene expression — a form of retrograde mitochondria-to-nucleus signaling unique among known peptides. 5-Amino-1MQ (5-Amino-1-methylquinolinium; CAS 42464-96-0; MW 159.21 g/mol; C₁₀H₁₁N₂⁺; PubChem CID 950107) is a membrane-permeable small-molecule inhibitor of Nicotinamide N-Methyltransferase (NNMT) with an IC₅₀ of ~1.2 µM, the first selective NNMT inhibitor developed (University of Texas, 2017). By preserving S-adenosylmethionine (SAM) and redirecting nicotinamide to the NAD⁺ salvage pathway, 5-Amino-1MQ elevates intracellular NAD⁺ specifically in white adipose tissue, activating SIRT1 and PGC-1α and shifting adipocyte metabolism from lipogenesis toward fatty acid oxidation. The combination creates a dual-mechanism metabolic profile: MOTS-C contributes exercise-mimetic AMPK activation and nuclear retrograde signaling from the mitochondrial dimension, while 5-Amino-1MQ targets the NAD⁺ salvage pathway and adipose NNMT enzymatic axis — together covering skeletal muscle, white adipose, and mitochondrial-nuclear signaling in a unified research formulation.
Clinical Research Indications
This metabolic blend is studied across multiple overlapping and complementary domains of energy homeostasis research:
- Metabolic Syndrome and Insulin Resistance: MOTS-C activates AMPK-driven GLUT4 upregulation and glucose uptake in skeletal muscle; 5-Amino-1MQ improves insulin sensitivity in adipocytes through SIRT1/NAD⁺ axis restoration, providing complementary muscle and adipose coverage.
- Obesity and Adipose Tissue Remodeling: 5-Amino-1MQ preclinical data show ~35% reduction in white adipose tissue mass over 11 days in obese mouse models via NNMT inhibition without altering food intake; MOTS-C contributes parallel AMPK-mediated fatty acid beta-oxidation in skeletal muscle.
- Longevity and Aging Research: MOTS-C circulating levels decline with age; supplementation in preclinical models improves metabolic flexibility, reduces bone loss via AMPK/RANKL pathway modulation, and activates nuclear antioxidant response element (ARE)-regulated gene programs. 5-Amino-1MQ’s SIRT1 activation has direct longevity-pathway relevance.
- Exercise Mimetics and Mitochondrial Biology: MOTS-C activates the same AMPK-PGC1α pathway engaged by physical exercise — the first mitochondria-encoded peptide shown to have systemic exercise-mimetic effects; 5-Amino-1MQ supports mitochondrial biogenesis through the same PGC-1α axis, with convergent but distinct upstream triggers.
Contraindications
- MOTS-C — Oxidation Sensitivity: The two methionine residues (Met-1 and Met-6) and single tryptophan (Trp-3) in the MOTS-C sequence are susceptible to oxidative degradation; handling under inert atmosphere and storage away from oxidizing agents is required to maintain biological integrity.
- 5-Amino-1MQ — Salt Form Awareness: The compound is supplied as a salt (iodide or chloride); the active free-base cation constitutes ~56–76% of total mass depending on the salt form. Dose calculations should be salt-form adjusted to avoid under- or over-dosing in quantitative research.
- Combined AMPK Activation — Hypoglycemia Risk in Insulin-Sensitized Models: Dual AMPK activation from both compounds may produce additive effects on glucose uptake; research designs in diabetic or metabolically compromised models should include glucose monitoring.
- MOTS-C Nuclear Translocation Timing: MOTS-C nuclear translocation is stress-dependent and follows a time-lag after metabolic stimulation; endpoint timing in gene expression experiments should account for this dynamic rather than assuming constitutive nuclear localization.
Mechanism of Action (MOA)
This blend engages two distinct and complementary metabolic regulatory axes — mitochondrial retrograde signaling (MOTS-C) and adipose NAD⁺ salvage pathway modulation (5-Amino-1MQ):
MOTS-C — Folate Cycle Interception and AMPK Activation
MOTS-C intercepts the folate and one-carbon (methionine) cycle within mitochondria, disrupting de novo purine biosynthesis and causing endogenous accumulation of AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) — a potent allosteric activator of AMP-activated protein kinase (AMPK). AMPK phosphorylation at Thr172 (confirmed ~2-fold increase in skeletal muscle within 30 minutes in preclinical studies) engages downstream catabolic pathways: upregulation of CPT1 (fatty acid transport into mitochondria), GLUT4 (glucose uptake), and PGC-1α (mitochondrial biogenesis). This folate-cycle-to-AMPK axis is mechanistically distinct from direct AMPK allosteric binding and represents a novel class of mitochondrial-to-cytosolic signaling.
MOTS-C — Nuclear Translocation and Retrograde Gene Regulation
Under metabolic stress, MOTS-C undergoes AMPK-dependent translocation from the mitochondrial/cytosolic compartment to the nucleus, where it binds promoter regions containing antioxidant response elements (ARE) and interacts with transcription factors NRF2 and ATF1/ATF7 to upregulate adaptive gene-expression programs. This retrograde mitochondria-to-nucleus signaling — mediated by MOTS-C’s hydrophobic core residues (⁸YIFY¹¹) rather than a classical nuclear localization signal — is without precedent among known small peptides and positions MOTS-C as a genuine “mitokine”: a mitochondrial hormone that communicates organelle metabolic status to the nuclear genome.
5-Amino-1MQ — NNMT Inhibition and NAD⁺ Salvage Pathway Restoration
NNMT (Nicotinamide N-Methyltransferase) catalyzes the SAM-dependent methylation of nicotinamide, consuming both the NAD⁺ precursor and reducing the SAM pool available for epigenetic methylation reactions. 5-Amino-1MQ inhibits NNMT with IC₅₀ ~1.2 µM and confirmed selectivity over NAMPT (>100 µM) and SIRT1 (>300 µM). Inhibition preserves nicotinamide for conversion to NAD⁺ via the NAMPT-NMN-NAD⁺ salvage pathway, elevating intracellular NAD⁺ selectively in adipocytes — activating SIRT1 deacetylase activity, AMPK signaling, and PGC-1α-driven mitochondrial biogenesis while suppressing lipogenic gene expression by 50–70% at therapeutic concentrations.
Synergistic Convergence at the AMPK-PGC-1α-SIRT1 Node
Both compounds independently converge on the AMPK-PGC-1α-SIRT1 metabolic regulatory hub through completely distinct upstream mechanisms: MOTS-C through mitochondrial folate cycle disruption and AICAR accumulation; 5-Amino-1MQ through NAD⁺ salvage restoration and adipocyte NNMT inhibition. This dual convergence — from mitochondrial retrograde signaling (MOTS-C) and cytosolic NAD⁺ availability (5-Amino-1MQ) — provides coordinated engagement of the SIRT1/AMPK axis across skeletal muscle and white adipose tissue compartments simultaneously, with non-overlapping upstream triggers.
Key Features & Specifications
Defining characteristics of this dual-mechanism mitochondrial and NAD⁺-pathway metabolic blend:
Chemical Analysis
| Property | Specification Reference Data |
|---|---|
| Component 1 — MOTS-C Sequence | Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg (MRWQEMGYIFYPRKLR; 16 AA) |
| MOTS-C CAS | 1627580-64-6 |
| MOTS-C Molecular Formula | C101H152N28O22S2 |
| MOTS-C Molecular Weight | 2,174.64 g/mol |
| MOTS-C PubChem CID | 146675088 |
| MOTS-C Synonyms | Mitochondrial ORF of the 12S rRNA type-c; MT-RNR1 peptide; mitokine MOTS-c |
| Component 2 — 5-Amino-1MQ | Small molecule (non-peptide); quaternary amine quinolinium salt; 5-amino-1-methylquinolinium; C₁₀H₁₁N₂⁺ |
| 5-Amino-1MQ CAS | 42464-96-0 (iodide salt) |
| 5-Amino-1MQ Molecular Formula | C10H11N2⁺ (free base cation) |
| 5-Amino-1MQ Molecular Weight | 159.21 g/mol (free base); 286.11 g/mol (iodide salt) |
| 5-Amino-1MQ PubChem CID | 950107 |
| 5-Amino-1MQ IC₅₀ (NNMT) | ~1.2 µM (selective; no NAMPT or SIRT1 inhibition at ≤100–300 µM) |
| Form / Variation | 20 MG Lyophilized Blend Vial (P-066) — 10 MG MOTS-C + 10 MG 5-Amino-1MQ |
Storage, Safety, and Handling
Storage Protocol
Store lyophilized blend at −20 °C, protected from light and oxygen; MOTS-C’s methionine (Met-1, Met-6) and tryptophan (Trp-3) residues are oxidation-sensitive — avoid exposure to peroxides, ozone, or prolonged air contact. 5-Amino-1MQ is a stable small molecule but hygroscopic in salt form; keep the vial sealed and desiccated until use. Once reconstituted, store at 2–8 °C and use within 14 days; the peptide component (MOTS-C) has lower reconstituted stability than larger lipidated peptides.
Handling & Compliance
Handle with standard laboratory PPE and aseptic technique throughout reconstitution. Note that 5-Amino-1MQ is supplied as a salt — dose calculations must account for salt form (iodide salt: ~56% active base per mg mass). MOTS-C is WADA-prohibited under the S0 Non-Approved Substances category. 5-Amino-1MQ has no published human pharmacokinetic or safety data; all published evidence derives from rodent models and in vitro studies. Institutional biosafety and ethics approval should be in place for research involving this blend.