MOTS-c

Overview

MOTS-c (Mitochondrial ORF of the Twelve S rRNA Type-c) is a mitochondrial-derived peptide (MDP) encoded within the 12S rRNA gene of mitochondrial DNA. Discovered in 2015 by Dr. Changhan Lee's laboratory at USC, MOTS-c represents a paradigm shift in our understanding of mitochondrial biology — demonstrating that mitochondria can encode signaling peptides that regulate nuclear gene expression.

MOTS-c is unique among known peptides in that it is encoded by the mitochondrial genome but exerts its effects primarily in the nucleus, where it translocates under conditions of metabolic stress. This retrograde mitochondrial-to-nuclear communication pathway represents a novel form of cellular signaling.

Chemical Profile

Mechanism of Action

MOTS-c regulates metabolic homeostasis primarily through activation of the AMP-activated protein kinase (AMPK) pathway. The peptide achieves AMPK activation indirectly by inhibiting the folate-methionine cycle at the level of MTHF (methylenetetrahydrofolate) metabolism, leading to accumulation of AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), an endogenous AMPK activator.

Under metabolic stress, MOTS-c translocates from the mitochondria to the nucleus, where it interacts with antioxidant response element (ARE)-containing genes. This nuclear translocation represents a unique stress-adaptive mechanism that links mitochondrial metabolic sensing to nuclear gene regulation.

AMPK activation by MOTS-c triggers a cascade of metabolic adaptations: enhanced glucose uptake, increased fatty acid oxidation, improved insulin sensitivity, and activation of cellular stress response pathways — collectively resembling the molecular effects of exercise.

Research Applications

• AMPK pathway activation and metabolic regulation
• Insulin sensitivity and glucose metabolism
• Exercise mimetic effects
• Mitochondrial-nuclear communication
• Folate-methionine cycle regulation
• Aging-related metabolic decline
• Skeletal muscle metabolism
• Mitochondrial-derived peptide biology

Handling & Reconstitution

1. 1Allow the vial and sterile water to reach room temperature (15–25°C).
2. 2Using a sterile syringe, withdraw the appropriate volume of sterile water.
3. 3Inject the water slowly along the inside wall of the vial — do not spray directly onto the powder.
4. 4Gently swirl the vial until the powder is fully dissolved. Do not shake vigorously.
5. 5Once reconstituted, store at 2°C – 8°C. Protect from light.
6. 6Use within 28 days after reconstitution.
7. 7Do not freeze reconstituted solution.