MOTS-c is a mitochondrial-encoded regulator of the AMPK pathway that controls skeletal muscle glucose metabolism[1]
The discovery paper for MOTS-c, published by the Cohen laboratory at USC, demonstrated that this 16-amino acid peptide is encoded within the mitochondrial 12S rRNA gene and is secreted from cells into circulation. In mouse skeletal muscle cells, MOTS-c activated AMPK through accumulation of AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), an endogenous AMPK activator, by inhibiting the de novo purine biosynthesis pathway. In vivo, MOTS-c evaluated in high-fat diet mice improved insulin sensitivity and reduced diet-induced obesity, demonstrating that mitochondrial-encoded peptides can regulate whole-body metabolic homeostasis.
Last verified: 2026-04-03
MOTS-c translocates to the nucleus under metabolic stress and modulates nuclear gene expression through the ARE pathway[2]
This follow-up study from the same laboratory demonstrated that MOTS-c undergoes nuclear translocation in response to oxidative stress, representing an unexpected mechanism for a mitochondrial-derived peptide. Once in the nucleus, MOTS-c interacts with the antioxidant response element (ARE) transcriptional machinery and with the transcription factor NRF2 (NFE2L2), upregulating antioxidant and cytoprotective gene networks. The nuclear translocation was observed in multiple human cell lines under glucose restriction and H2O2 challenge, and MOTS-c nuclear localization was confirmed by immunofluorescence and nuclear fractionation experiments.
Last verified: 2026-04-03
