Mitochondrial DNA-driven intercellular communication networks in post-infarction ventricular remodeling: the three-threshold model of cGAS-STING activation

Mitochondrial DNA (mtDNA) has long been recognized as an intracellular damage−associated molecular pattern, but emerging evidence reveals its role as an intercellular messenger driving post−infarction ventricular remodeling. This review systematically elaborates the transition of mtDNA from an “intracellular DAMP” to an “intercellular messenger” and proposes a conceptual framework termed the “three−threshold model”, which integrates existing evidence but requires direct experimental validation. The three thresholds are defined as the release threshold (mitophagy−controlled mtDNA leakage), the transmission threshold (efficiency of intercellular transfer), and the activation threshold (sensitivity of STING signaling). mtDNA is transferred between cells via four modes—naked mtDNA, Ambra1 + sEVs, mt−sEVs, and intact mitochondria—mediating inflammation, fibrosis, and vascular dysfunction, respectively. These pathological effects continuously lower all three thresholds through positive feedback loops, driving irreversible remodeling. Time−window−based combination strategies offer a new paradigm for precision intervention. This framework integrates the entire process from mtDNA generation to intercellular transfer and downstream signaling, providing a systematic basis for precision intervention in post−infarction remodeling. Importantly, several components of this model are based on preliminary or indirect evidence and await independent confirmation.