MOTS-c is a 16-amino-acid mitochondrial-encoded peptide identified in the 12S rRNA open reading frame that has attracted attention for its effects on cellular metabolism in preclinical models. Animal and cellular studies report that MOTS-c modulates metabolic homeostasis, regulates stress-responsive nuclear gene expression, influences insulin-sensitive pathways in skeletal muscle, and can alter inflammatory signaling in disease models; mechanistic work highlights nuclear-mitochondrial signaling, transcriptional regulation of metabolic genes, and improvements in mitochondrial function in nonclinical systems as central themes. Reviews of mitochondrial-derived peptides contextualize MOTS-c within an emerging class of bioactive micropeptides that link mitochondrial state to whole-cell adaptive responses.

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