The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress

This study published in Cell Metabolism revealed a previously unknown mechanism of the MOTS-c peptide: its ability to translocate from mitochondria to the nucleus in response to metabolic stresses. It is one of the first demonstrations that mitochondrial-derived peptides can act directly as nuclear transcriptional regulators.

The authors demonstrated that, under conditions such as glucose restriction, hypoxia, or oxidative stress, MOTS-c migrates to the nucleus and regulates the expression of a network of genes involved in:

• Antioxidant response (including NRF2 target genes)
• Amino acid metabolism and purine biosynthesis
• Adaptation to metabolic stress mediated by AMPK

This finding fundamentally expanded the understanding of mitochondria-nucleus communication, showing that cross-talk involves not only indirect messengers (such as ROS or metabolites) but also direct peptide messengers encoded by the mitochondrial genome. MOTS-c emerges as an integrating transcriptional regulator of the cellular response to metabolic stress.

The pathophysiological implications are broad: by integrating mitochondrial and nuclear signals, MOTS-c may coordinate adaptive responses under conditions of aging, obesity, diabetes, and neurodegenerative diseases, consolidating its relevance as a therapeutic target in metabolic disorders.