MOTS-c: a context-dependent mitochondrial stress signal in homeostasis and tumor

Mitochondria are increasingly recognized not only as metabolic organelles but also as sources of mitochondrial genome-encoded signals that communicate with the nucleus and distant tissues. MOTS-c, a 16-amino-acid peptide encoded within the mitochondrial 12 S rRNA region, is a representative mitochondria-derived peptide linking mitochondrial stress, metabolic state, and adaptive cellular responses. This Review summarizes the discovery, origin, structural features, and signaling mechanisms of MOTS-c, together with its reported roles in redox control, apoptosis regulation, inflammation, endothelial protection, exercise adaptation and metabolic homeostasis. We also assess the heterogeneous clinical evidence on MOTS-c abundance and discuss potential biological and methodological sources of inconsistency. Finally, we examine the emerging but still limited evidence connecting MOTS-c to tumor biology, including metabolic reprogramming, redox adaptation, ferroptosis regulation, microenvironmental remodeling, immune modulation, tumor self-protection, and therapeutic resistance. This review aims to delineate the biological functional scope of MOTS-c, identify disease contexts in which MOTS-c signaling may be therapeutically beneficial or potentially detrimental, and discuss the molecular mechanisms that may underlie its context-dependent effects. MOTS-c should be viewed as a context-dependent mitochondria-derived stress signal whose actions are shaped by cell type, subcellular localization, metabolic state, inflammatory milieu, and disease context. Through its established roles in redox control, stress adaptation, inflammatory regulation, and cellular homeostasis, MOTS-c may influence tumor microenvironment remodeling, tumor cell self-protection, and therapeutic resistance. Future studies should establish standardized detection methods, trafficking routes, molecular targets, and cell-specific effects of MOTS-c, particularly across tumor and stromal compartments.