Mitochondrial open-reading-frame of the 12S rRNA type-c peptide (MOTS-c)

MOTS-c is a mitochondria-derived peptide consisting of 16 amino acids encoded by an open reading frame within the mitochondrial 12S rRNA gene. It acts as a hormone-like regulator with significant roles in cellular energy homeostasis, primarily by activating the AMPK pathway, which increases glucose uptake and fatty acid oxidation. This action improves insulin sensitivity and helps maintain overall metabolic balance. MOTS-c exerts tissue-specific functions including promoting osteoblast activity while inhibiting osteoclast differentiation in bone tissue—suggesting potential utility against osteoporosis—and modulating lipid accumulation in liver and adipose tissues. It also has demonstrated protective roles against inflammation-induced cognitive impairment when administered centrally but does not cross the blood-brain barrier efficiently without modification. In cardiovascular contexts, lower endogenous levels are associated with impaired endothelial function; supplementation improves vascular responsiveness via anti-inflammatory mechanisms. Preclinical evidence suggests that it may enhance survival during severe infections by boosting macrophage bactericidal capacity. Levels decline with age, linking reduced MOTS-c activity to increased susceptibility to age-related diseases such as diabetes, neurodegeneration, osteoporosis, cardiovascular dysfunctions, infection risk increase due to immunosenescence—and possibly even longevity regulation through nuclear-mitochondrial crosstalk.

Other names

mitochondrial-derived peptide MOTS-cmitokine MOTS-cmitochondrial ORF of the 12S rRNA type-C peptide

Activation of AMP-activated protein kinase (AMPK) pathway to stimulate glucose uptake, enhance fatty acid oxidation, and improve metabolic flexibility. Inhibition/modulation of pro-inflammatory cytokines via AMPK activation. Regulation/inhibition through TGF-beta/Smad signaling pathway in bone cells for osteogenic differentiation and anti-resorptive effects on bone tissue. Retrograde signaling from mitochondria to nucleus affecting gene expression under metabolic stress.