MOTS‑c is a tiny protein made by mitochondria that gets released when you’re stressed or exercising. It moves into the cell nucleus and turns on genes that help the body handle stress, improve energy use, and protect against age‑related problems. Most of its effects come from activating a pathway (Folate‑AICAR‑AMPK) that boosts metabolism, reduces insulin resistance, and calms inflammation.

MOTS-c is a peptide encoded by the short open reading frame of the mitochondrial 12S rRNA gene. It is significantly expressed in response to stress or exercise and translocated to the nucleus, where it regulates the expression of stress adaptation-related genes with antioxidant response elements (ARE). MOTS-c mainly acts through the Folate-AICAR-AMPK pathway, thereby influencing energy metabolism, insulin resistance, inflammatory response, exercise, aging and aging-related pathologies. Because of the potential role of MOTS-c in maintaining energy and stress homeostasis to promote healthy aging, especially in view of the increasing aging of the global population, it is highly pertinent to summarize the relevant studies. This review summarizes the retrograde signaling of MOTS-c toward the nucleus, the regulation of energy metabolism, stress homeostasis, and aging-related pathological processes, as well as the underlying molecular mechanisms.