Description
Summary Abstract
MOTS-C (Mitochondrial ORF of the 12S rRNA Type-C; MT-RNR1 peptide; humanin-related MDP) is a 16-amino acid peptide of mitochondrial origin, first characterized by Lee et al. in 2015. Translated from a short open reading frame (sORF) within the 12S ribosomal RNA gene (MT-RNR1) of the mitochondrial genome using the standard nuclear genetic code, MOTS-C is the prototype for the class of mitochondrial-derived peptides (MDPs) with systemic hormonal activity. It circulates in human plasma, declines with age, and rises approximately 1.5-fold following acute high-intensity exercise. The primary mechanism involves inhibition of the folate cycle enzyme ATIC, driving AICAR accumulation and AMPK activation — a pathway mechanistically analogous to, but upstream and distinct from, metformin’s Complex I route. Phase 1b clinical trial data for the stabilized analog CB4211 in NAFLD patients with type 2 diabetes show ALT reduction of 21%, AST reduction of 28%, and 6% fasting glucose reduction versus placebo. MOTS-C is prohibited under WADA S2 and cannot be compounded at FDA 503B outsourcing facilities.
Clinical Indications
MOTS-C has generated human clinical and mechanistic evidence across metabolic, aging, and exercise biology domains:
- NAFLD / Metabolic Liver Disease: CB4211 (stabilized MOTS-C analog, NCT03998514) in Phase 1b: ALT −21%, AST −28% vs placebo; fasting glucose −6% in NAFLD patients with type 2 diabetes — establishing hepatoprotective and glucose-regulatory signals in humans.
- Insulin Resistance & Type 2 Diabetes: MOTS-C in mouse models of diet-induced obesity improved insulin sensitivity comparably to metformin; the AICAR/AMPK mechanism supports glucose transporter (GLUT4) upregulation independent of insulin signaling.
- Skeletal Muscle Preservation / Sarcopenia: Via myostatin suppression (CK2 → PTEN inhibition → AKT → FOXO1) and AMPK-mediated substrate utilization, MOTS-C is studied in sarcopenia models and exercise physiology research.
- Aging & Longevity: Plasma MOTS-C declines with age in both humans and rodents; exogenous MOTS-C reversed age-associated insulin resistance in aged mice; the molecule is a candidate longevity-associated mitokine.
- Exercise Mimetic Biology: MOTS-C is the first endogenous peptide identified as rising substantially with acute exercise, informing research on exercise-mimetic pharmacology and mitochondrial stress signaling.
Contraindications
- WADA-Governed Athletic Contexts: MOTS-C is prohibited under WADA S2 (Peptide Hormones, Growth Factors, and Related Substances), in- and out-of-competition; use is incompatible with competitive athletics governed by WADA code.
- 503B Compounding Restriction: FDA has placed MOTS-C on the cannot-be-compounded list for 503B outsourcing facilities; clinical availability requires state-licensed 503A compounding pharmacies, subject to state pharmacy board regulations.
- K14Q SNP Populations (Reduced Response): The m.1382A>C SNP (K14Q), prevalent in Northeast Asian populations, may reduce MOTS-C nuclear localization and transcription factor binding capacity; researchers studying these cohorts should consider genotyping for this variant to ensure interpretable metabolic endpoint data.
Mechanism of Action (MOA)
MOTS-C initiates a signaling cascade beginning in the mitochondrial matrix and extending to the nucleus via two principal pathway arms:
Folate Cycle → AICAR → AMPK Activation
MOTS-C inhibits ATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase) in the folate cycle, causing intracellular accumulation of AICAR. AICAR directly activates AMP-activated protein kinase (AMPK) — the master energy sensor — driving fatty acid oxidation, GLUT4-mediated glucose uptake, and mitochondrial biogenesis via PGC-1α. This route is mechanistically distinct from metformin’s Complex I inhibition and does not carry associated lactic acidosis risk.
Nuclear Translocation & Nrf2/ARE
Under cellular stress, MOTS-C translocates to the nucleus where it binds and activates the Nrf2/ARE (antioxidant response element) pathway, upregulating HO-1, NQO1, and other cytoprotective genes. Concurrently, MOTS-C activates CK2 → PTEN inhibition → AKT → FOXO1 exclusion, suppressing myostatin gene expression to promote skeletal muscle mass retention and oppose atrophy.
White Adipose Tissue Browning
MOTS-C upregulates UCP1 and PGC-1α in white adipose tissue (WAT), promoting a thermogenic, brown-adipose-like phenotype with enhanced energy expenditure. This WAT browning effect, combined with AMPK-driven fatty acid oxidation, positions MOTS-C as a multi-axis metabolic effector with distinct adipose and skeletal muscle activity.
Key Features & Specifications
MOTS-C is the first mitochondrial-genome-encoded circulating peptide hormone characterized with systemic endocrine activity:
Chemical Analysis
| Property | Specification Reference Data |
|---|---|
| Sequence | Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg (MRWQEMGYIFYPRKLR) |
| CAS Number | Not assigned (contact supplier) |
| Molecular Formula | C105H165N33O23S2 |
| Molecular Weight | ~2,174.7 Da |
| PubChem CID | Not established |
| Synonyms | MOTS-C; Mitochondrial ORF 12S rRNA Type-C; MT-RNR1 peptide; humanin-related MDP |
| Genetic Origin | MT-RNR1 sORF, mitochondrial genome (12S rRNA gene) |
| Form / Variation | 10 MG Lyophilized (P-028) / 40 MG Lyophilized (P-052) |
Storage, Safety, and Handling
Storage Protocol
Store lyophilized MOTS-C at −20°C, protected from light and humidity; seal tightly after each use as the peptide contains multiple photosensitive aromatic residues (Trp at position 3, Tyr, Phe). Reconstituted solution should be refrigerated at 2–8°C and used within 14 days; do not freeze reconstituted material. Reconstitute with sterile water for injection or bacteriostatic water by gentle inversion or rolling — do not vortex. Minimize ambient light exposure during reconstitution and handling to prevent Trp oxidation.
Handling & Compliance
Prepare solutions under sterile technique with gloves and appropriate PPE. The CB4211 Phase 1a/1b safety program established a favorable tolerability profile for MOTS-C analogs; the most common reported events were mild injection site reactions. MOTS-C is prohibited under WADA S2 in- and out-of-competition. It cannot be compounded at FDA 503B outsourcing facilities; researchers and clinicians requiring clinical-grade preparations should work through state-licensed 503A compounding pharmacies. Genotyping for K14Q (m.1382A>C) is advisable in Northeast Asian population studies.