The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance

This publication in Cell Metabolism represented the discovery of MOTS-c (Mitochondrial Open reading frame of the Twelve S rRNA type-c), a 16-amino acid peptide encoded by mitochondrial DNA that functions as a metabolism-regulating hormone. The work by Changhan Lee's group at USC was pioneering in demonstrating that mitochondria can encode peptides with systemic hormonal function.

The researchers demonstrated that MOTS-c is secreted into the bloodstream and acts primarily on skeletal muscle, where it:

• Activates the AMPK signaling pathway (cellular energy sensor)
• Inhibits the folate pathway and de novo purine biosynthesis
• Accumulates the metabolic intermediate AICAR, an endogenous AMPK activator
• Improves insulin sensitivity and glucose uptake

In mice fed a high-fat diet, MOTS-c treatment prevented weight gain and insulin resistance induced by the diet. Even in already obese animals, MOTS-c administration improved glycemic homeostasis. Circulating MOTS-c levels decreased with aging and obesity, suggesting that its deficiency may contribute to age-related metabolic diseases.

This study inaugurated the concept of mitochondrial-derived peptides (MDPs) as a new class of hormones, significantly expanding our understanding of mitochondria-nucleus communication and the role of mitochondria beyond energy production. MOTS-c is frequently described as an "exercise mimetic" because it mimics many of the metabolic adaptations induced by physical activity.