MOTS-c

MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA type-c) is a 16 amino acid peptide encoded within the mitochondrial genome in a non-canonical open reading frame of the 12S ribosomal RNA gene (MT-RNR1). Its identification by Lee et al. (Cell Metabolism, 2015) established MOTS-c as a mitochondrial-derived peptide (MDP) — a founding member of a new class of peptide hormones encoded by the mitochondrial genome and acting as retrograde signals communicating mitochondrial functional state to the cytoplasm and nucleus.

The primary mechanism of MOTS-c action involves inhibition of folate-dependent one-carbon metabolism, specifically targeting ATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase) — the enzyme that converts AICAR to IMP in the de novo purine synthesis pathway. ATIC requires 10-formyltetrahydrofolate as a methyl donor; MOTS-c inhibition of this folate-dependent step causes AICAR to accumulate intracellularly. Accumulated AICAR is phosphorylated to ZMP by adenosine kinase, and ZMP activates AMPK by mimicking AMP at the gamma subunit regulatory domains — the identical mechanism by which exogenous AICAR activates AMPK.

This mechanistic connection between MOTS-c and AICAR is both scientifically important and practically useful for research design: using AICAR alongside MOTS-c in parallel experiments, with Compound C (AMPK inhibitor) as a pathway control, allows direct quantification of the AMPK-dependent fraction of MOTS-c's biological effects versus any AICAR/AMPK-independent biology.

A second, AMPK-independent MOTS-c mechanism has been identified: under cellular stress conditions (UV radiation, glucose deprivation, oxidative stress), MOTS-c translocates from the cytoplasm to the nucleus, where it modulates gene expression through interaction with stress-response transcription factors including the Nrf2/ARE (antioxidant response element) system. This nuclear function activates antioxidant and stress-protective gene programmes independently of the AICAR/AMPK pathway — providing a distinct research dimension accessible by studying MOTS-c under stress conditions compared to baseline metabolic conditions.

Plasma MOTS-c concentrations are exercise-regulated and age-dependent. Reynolds et al. (Nature Communications, 2021) published that circulating MOTS-c increases significantly following acute exercise in humans — establishing MOTS-c as an exercise-induced mitokine that may contribute to the systemic metabolic adaptations of physical training. Age-related decline in MOTS-c parallels declining mitochondrial function and exercise capacity, positioning MOTS-c within the exercise mimetic and longevity research frameworks alongside AICAR and SLU-PP-322.

AMPK downstream biology confirmed by MOTS-c treatment: phospho-ACC (Ser79) by Western blot; phospho-AMPK (Thr172); GLUT4 membrane translocation (2-NBDG uptake assay); PGC-1alpha expression (qRT-PCR, Western); mtDNA copy number (qPCR); and oxygen consumption rate by Seahorse XF analysis.

MW: 2174.57 g/mol. CAS: 1450580-21-8. Reconstitute in bacteriostatic water at 1mg/mL. Store lyophilised at -20°C. For laboratory and analytical research purposes only.

For AMPK pathway comparison research: run MOTS-c (1-10uM) alongside AICAR (0.5-2mM) and vehicle control in the same cell preparation. Western blot for phospho-AMPK (Thr172), phospho-ACC (Ser79), and phospho-TSC2 (Thr1227) as downstream AMPK targets. Include Compound C (10uM, 30 min pre-treatment) as AMPK inhibitor to confirm AMPK-dependence of observed effects. For nuclear translocation research, expose cells to glucose-free HBSS for 2 hours before MOTS-c treatment (10uM), then perform immunofluorescence with anti-MOTS-c antibody (if available) and DAPI nuclear counterstain, quantifying nuclear-to-cytoplasmic ratio by confocal imaging. MW: 2174.57 g/mol. CAS: 1450580-21-8. Reconstitute in bacteriostatic water at 1mg/mL. Store lyophilised at -20°C. For laboratory and analytical research purposes only.