MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c)

MOTS-c is a mitochondrial-derived peptide (MDP) encoded within the 12S rRNA gene of mitochondrial DNA. Discovered in 2015 by Dr. Pinchas Cohen's laboratory at USC, it represents a new class of peptides that originate from the mitochondrial genome rather than nuclear DNA. This discovery challenged the dogma that mitochondria primarily function as simple energy factories, revealing they also produce bioactive peptides that influence systemic metabolism. MOTS-c has been shown to regulate metabolic homeostasis, enhance insulin sensitivity, and may play roles in exercise adaptation and aging.

MOTS-c acts through several interconnected metabolic pathways: **AMPK Activation:** MOTS-c activates AMP-activated protein kinase (AMPK), the master regulator of cellular energy homeostasis. AMPK activation promotes glucose uptake, fatty acid oxidation, and mitochondrial biogenesis while inhibiting energy-consuming processes. **Folate-Methionine Cycle Regulation:** MOTS-c inhibits the folate cycle, leading to accumulation of AICAR (an AMPK activator). This metabolic reprogramming affects one-carbon metabolism and may influence epigenetic regulation. **Nuclear Translocation:** Under metabolic stress, MOTS-c translocates to the nucleus where it regulates gene expression through interaction with transcription factors, including those controlling antioxidant response elements. **Insulin Sensitivity Enhancement:** Through AMPK-dependent and independent mechanisms, MOTS-c improves glucose uptake and insulin sensitivity in skeletal muscle and other tissues.