Metabolic stress, mitochondrial DNA release and the nutritional regulatory potential of the cGAS-STING pathway during high-intensity interval training

High-intensity interval training (HIIT) is widely adopted for its time efficiency, yet it imposes intense metabolic stress that may compromise mitochondrial integrity and could promote mitochondrial DNA (mtDNA) release into the cytosol, where mislocalized mtDNA may act as a damage-associated molecular pattern (DAMP) engaging the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, a central hub of innate immunity. This review examines, across the central nervous, cardiovascular, respiratory, and skeletal muscle systems as well as immune and metabolic organs such as the liver and adipose tissue, whether and where HIIT may engage this “metabolic stress–mtDNA–cGAS-STING” axis to yield organ-specific outcomes—from beneficial cardiometabolic and musculoskeletal adaptation to adverse neuro-, hepato-, and adipo-inflammatory responses under excessive load. Given this duality, targeted nutritional strategies, such as mitochondria-protective agents, specific phytochemicals, and compounds that modulate autophagy or the cGAS-STING pathway itself, hold potential to fine-tune this signaling cascade, supporting optimal training adaptation by mitigating inflammatory risks. This paper proposes a unifying, hypothesis-generating framework by integrating evidence from multiple organ systems: the metabolic stress-mtDNA-cGAS-STING signaling axis may serve as a common mechanism underpinning the systemic bidirectional effects of HIIT, although direct in-human evidence for cytosolic mtDNA release and distal cGAS-STING activation during exercise remains limited. Elucidating this signaling axis is critical for developing personalized HIIT intervention strategies to maximize therapeutic benefits.