Discovery: Dr. Pinchas Cohen and the Keck School of Medicine (2015)

MOTS-c was identified and characterized by Dr. Pinchas Cohen’s team at the Keck School of Medicine, University of Southern California (USC). The research findings were published in 2015 in the prestigious scientific journal *Cell Metabolism* (Lee et al., 2015), providing the scientific foundation for further research on this molecule.
The publication describes MOTS-c as a mitochondrially encoded peptide that regulates glucose and lipid metabolism and suggests its role in systemic metabolic homeostasis.

The First Mitochondrially Encoded Peptide with Metabolic Effects

MOTS-c belongs to the growing family of mitochondria-derived peptides (MDPs), which also includes Humanin and SHLP1-6. However, MOTS-c is unique in its ability to translocate from the mitochondria to the cell nucleus and directly modulate gene expression—a property that is unprecedented in the MDP class.

AMPK Activation and Regulation of Cellular Energy

The key biochemical target of MOTS-c is the activation of AMPK (AMP-activated protein kinase) —the central sensor of a cell’s energy status. AMPK is a so-called “energy sensor” that is activated when the ATP/AMP ratio in the cell decreases and coordinates metabolic processes:

• Stimulation of fatty acid oxidation – increased energy expenditure from fat stores
• Increased insulin sensitivity – improved glucose utilization in muscle cells
• Regulation of mitophagy – selective removal of damaged mitochondria
• Inhibition of gluconeogenesis – reduction in glucose production in the liver (in vitro models)

Research in cell cultures and mouse models suggests that MOTS-c activates the AMPK pathway independently of traditional energy-sensing mechanisms.

MOTS-c translocation: mitochondria → cytoplasm → nucleus

One of the most significant scientific findings regarding MOTS-c is its ability to translocate from the mitochondria to the cytoplasm and subsequently to the cell nucleus —particularly under conditions of metabolic stress (e.g., during physical exertion). Upon entering the nucleus, MOTS-c interacts with transcription factors and modulates the expression of genes involved in metabolism, defense mechanisms against oxidative stress, and cellular energy regulation.
This intracellular transport mechanism has been documented both in vitro and in animal models of physical exercise (Cohen et al., 2015, 2019).

Research on Insulin Sensitivity (Animal Models)

In studies using mouse models with induced insulin resistance, MOTS-c was investigated in relation to:

• Regulation of glucose utilization in skeletal muscle
• Effects on glycolysis and fatty acid oxidation
• Expression of glucose transporters (GLUT4) in muscle cells

Results from studies in animal models suggest potential metabolic significance; however, these findings cannot be extrapolated to human use.

Research on Physical Performance and Endurance

In preclinical models of physical exercise, researchers observed an improvement in endurance performance in mice administered MOTS-c. Cohen and colleagues (animal models) documented:

• Increasing Performance on a Treadmill (Time to Exhaustion)
• Improved mitochondrial function in muscle cells
• Activation of genes involved in mitochondrial biogenesis

These results are the subject of further scientific research.