MOTS-c

MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA type-c) is a 16-amino acid peptide encoded by the mitochondrial genome, discovered by Lee and colleagues at the University of Southern California in 2015. It was the first mitochondrial-derived peptide shown to have systemic metabolic effects, representing a paradigm shift in understanding mitochondrial signaling. MOTS-c is encoded within the 12S rRNA gene of mitochondrial DNA and is one of several mitochondrial-derived peptides (MDPs) that function as retrograde signals from mitochondria to the nucleus and other cellular compartments.

The primary in-vitro effects of MOTS-c involve activation of the AMPK (5' adenosine monophosphate-activated protein kinase) signaling pathway, a master regulator of cellular energy homeostasis. Research has characterized MOTS-c for glucose-uptake and fatty-acid-oxidation assay markers in rodent cell-culture models of metabolic-parameter research. The peptide has been described as an "exercise mimetic" due to its ability to activate metabolic pathways that are typically stimulated by physical exercise, including AMPK-dependent and folate-methionine cycle pathways.

More recent research has revealed that MOTS-c translocates to the nucleus under conditions of metabolic stress, where it regulates gene expression through interaction with antioxidant response elements (AREs). Studies have also identified correlations between circulating MOTS-c levels and physical fitness, aging, and metabolic disease states, suggesting a role as a mitochondrial-encoded hormone (mitokine) that communicates cellular metabolic status to systemic physiology.