MOTS-C

MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a 16-residue peptide, MRWQEMGYIFYPRKLR, encoded by a short open reading frame within the mitochondrial 12S rRNA gene. It belongs to the family of mitochondrial-derived peptides that also includes humanin, and its identification supported the view that the mitochondrial genome encodes signaling peptides in addition to its classical protein-coding genes. The synthetic peptide has the formula C101H152N28O22S2 and a molar mass of about 2,174.6 g/mol.

MOTS-C in the research literature

In the founding cell and mouse studies, MOTS-c was reported to act primarily on skeletal muscle, where it inhibited folate one-carbon metabolism and the tethered de novo purine biosynthesis pathway, leading to AMPK activation. Later cell work showed that under metabolic stress, such as glucose restriction, the peptide translocates to the nucleus in an AMPK-dependent manner, regulates a broad set of genes including those carrying antioxidant response elements, and interacts with the stress-responsive transcription factor NRF2.

In mouse models, MOTS-c has been studied for its effects on skeletal-muscle metabolic adaptation in young, middle-aged and old animals, on nuclear genes related to metabolism and proteostasis, and on myoblast adaptation to metabolic stress. An unbiased plasma metabolomics study in diet-induced mouse models reported changes in sphingolipid, monoacylglycerol and dicarboxylate metabolism pathways.