MOTS-c — Published Research

MOTS-c was identified in 2015 as a peptide encoded within a short open reading frame in the 12S rRNA region of mitochondrial DNA. Unlike nuclear-encoded peptides, MOTS-c is translated using the mitochondrial genetic code and exported to the cytoplasm and circulation. Plasma MOTS-c levels have been measured in humans and show variation with age and metabolic state. The discovery of MOTS-c expanded the concept of mitochondria as signaling organelles that communicate with the nucleus and other tissues.

Lee C et al. “The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance.” Cell Metab. 2015. PubMed

MOTS-c activates AMP-activated protein kinase (AMPK), the master regulator of cellular energy homeostasis. The mechanism involves MOTS-c inhibition of the folate-methionine cycle, specifically by binding to and inhibiting methionine adenosyltransferase 2A (MAT2A), leading to decreased S-adenosylmethionine (SAM) levels and de-repression of AMPK. AMPK activation then stimulates glucose uptake, fatty acid oxidation, and mitochondrial biogenesis while inhibiting lipogenesis and gluconeogenesis.

Reynolds JC et al. “MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis.” Nat Commun. 2021. PubMed

Under metabolic stress conditions, MOTS-c translocates to the nucleus where it regulates gene expression involved in cellular stress responses. Nuclear MOTS-c interacts with ARE (antioxidant response element)-containing gene promoters and modulates transcription of genes including NRF2 targets. This represents a unique form of retrograde signaling where a mitochondrial-encoded peptide directly regulates nuclear gene transcription. Exercise increases MOTS-c nuclear translocation in skeletal muscle cells.

Kim KH et al. “MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism.” Free Radic Biol Med. 2018. PMC