Research of ferroptosis in myocardial ischemia/reperfusion injury (MIRI) using mitochondrial viscosity as a nexus holds great promise for MIRI therapeutics. However, high precision visualizing mitochondrial viscosity remains a formidable task owing to the debilitating electrostatic interaction caused by damaged mitochondrial membrane potential. Herein, we proposed a dual-locking mitochondrial targeting strategy that incorporates the idea of electrostatic forces and probe-protein molecular docking. Even in the damaged mitochondria, stable and precise visualization of mitochondrial viscosity in triggered and medicated MIRI was achieved owing to the sustained driving forces (pi-cation, pi-alkyl interactions etc.) between the developed probe CBS and mitochondrial membrane protein. Moreover, complemented by the western blot technology, we confirmed that ferrostatin-1 exerts its therapeutic effect on MIRI by improving the system xc−/GSH/GPX4 antioxidant system, confirming the therapeutic value of ferroptosis in MIRI. This work presents a new strategy for developing robust mitochondrial probes, thereby advancing the treatments for MIRI.
Published in: "Angewandte Chemie International Edition".