Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging

MOTS-c (Mitochondrial Open reading frame of the Twelve S rRNA type-c) is a biologically active peptide encoded by the mitochondrial 12S rRNA gene. Discovered in 2015, it represents a critical link in mitochondrial-nuclear communication. While mitochondria were traditionally viewed as simple energy-producing organelles, the discovery of MOTS-c highlights their role as active regulators of cellular stress responses, metabolism, and aging. MOTS-c expression is triggered by exercise and metabolic stress, and its levels typically decline with age, making it a subject of intense interest for promoting healthy aging.

Under resting conditions, MOTS-c is primarily located outside the nucleus. However, in response to metabolic stress—such as glucose restriction or oxidative stress—it rapidly translocates into the nucleus. This process is dependent on AMPK (AMP-activated protein kinase) signaling. Once in the nucleus, MOTS-c interacts with transcription factors like NRF2 and ATF1/ATF7 to modulate the expression of genes containing antioxidant response elements (ARE).

Central to its function is the Folate-AICAR-AMPK pathway. MOTS-c influences the folate cycle and de novo purine biosynthesis, leading to the accumulation of AICAR, which subsequently activates AMPK. This activation creates a positive feedback loop, as AMPK both mediates the metabolic effects of MOTS-c and promotes its nuclear translocation. Through this axis, MOTS-c regulates SIRT1 and PGC-1α, which are essential for mitochondrial biogenesis and the suppression of pro-inflammatory responses.

MOTS-c has demonstrated broad therapeutic potential in preclinical models. It improves insulin sensitivity, prevents diet-induced obesity, and enhances physical performance in aged mice. Furthermore, it exhibits anti-inflammatory properties by inhibiting the NF-κB pathway and reducing the production of pro-inflammatory cytokines. These effects are particularly relevant for age-related pathologies, including osteoporosis, cardiovascular dysfunction, and neurodegenerative conditions. Because exercise naturally stimulates MOTS-c production, it is considered a key mediator of the health benefits associated with physical activity.