Mots C: Mechanism of Action

Mechanism of Action

Primary Pathway: Folate → AICAR → AMPK ("Master Metabolic Switch")

MOTS-c inhibits the folate cycle at 5-methyltetrahydrofolate (5Me-THF), blocking de novo purine biosynthesis. This leads to accumulation of AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), which mimics AMP and directly activates AMPK.[1]

1. MOTS-c → inhibits folate cycle (5Me-THF)
2. Blocked purine synthesis → AICAR accumulation
3. AICAR (AMP mimetic) → direct AMPK activation
4. AMPK → ACC phosphorylation → fatty acid oxidation
5. AMPK → GLUT4 translocation → enhanced glucose uptake

Direct Binding Partners

Target	Binding Domain	Functional Consequence
CK2α	Cationic tail (¹³RKLR¹⁶)	Skeletal muscle insulin sensitization; K14Q polymorphism reduces this binding[7]
Raptor (mTORC1)	Hydrophobic core (⁸YIFY¹¹)	Allosteric mTORC1 inhibition → shifts T-cell differentiation from Th1 to FOXP3+ Tregs[8]
Nrf2 (nuclear)	Direct chromatin binding	Nuclear translocation under stress → ARE → antioxidant gene expression (~1,000 genes)[3]

Nuclear Translocation

Under metabolic stress (glucose restriction, oxidative stress), MOTS-c translocates from mitochondria/cytoplasm to the nucleus. It lacks a canonical nuclear localization signal (NLS) — instead relying on its hydrophobic core for entry. Once nuclear, it binds chromatin at ARE via Nrf2 transcription factor to regulate antioxidant gene expression.[3]

SIRT1/PGC-1α Pathway

MOTS-c increases intracellular NAD+ → activates SIRT1 → PGC-1α deacetylation → mitochondrial biogenesis and anti-inflammatory cytokine regulation.[6]

MAPK/ERK (Tissue-Dependent)

• Adipose tissue: Activates ERK → UCP1/PGC-1α → thermogenesis/browning of white fat[9]
• Inflammation: Inhibits ERK/JNK/p38 → suppresses NF-κB[10]

TGF-β/SMAD (Bone)

In osteoblasts: upregulates TGF-β1/2 and SMAD7 → Type I collagen synthesis → osteogenic differentiation.[11]

vs. Related Compounds

Compound	Origin	Key Difference
MOTS-c	mtDNA 12S rRNA (MT-RNR1)	Targets folate cycle, nuclear translocation, exercise mimetic
Humanin	mtDNA 16S rRNA	Cytoprotective but does not target folate or nuclear gene expression
CB4211 (analog)	Synthetic (CohBar)	Engineered for improved stability/longer half-life; Phase 1b completed