MOTS-c is a 16-amino-acid peptide encoded by a short open reading frame (sORF) within the mitochondrial 12S rRNA. MOTS-c, which is a contraction of mitochondrial open reading frame of the 12S rRNA-c, regulates insulin sensitivity and metabolic homeostasis with its primary target organ being skeletal muscle. The cellular action of MOTS-c is to inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to activation of AMP-activated protein kinase (AMPK), a central regulator of energy homeostasis. In mouse models, MOTS-c treatment prevents age dependent and high fat diet-induced insulin resistance, as well as diet induced obesity.
Lee et al (2015) The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 21(3) 443 PMID: 25738459
Wei et al (2020) Mitochondrial-Derived Peptide MOTS-c Attenuates Vascular Calcification and Secondary Myocardial Remodeling via Adenosine Monophosphate-Activated Protein Kinase Signaling Pathway. Cardiorenal Med. 10(1) 42 PMID: 31694019
Reynolds et al (2021) MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 12(1) 470 PMID: 33473109