A dual-targeted fluorescent probe reveals the changes in the polarity of endosomes and mitochondria during ferroptosis

Ferroptosis, which participates in multiple pathophysiological processes, is executed by iron-dependent phospholipid peroxidation. Due to any biomolecular interaction or change resulting in modification of the local microenvironment, deep insights into these variations are indispensable for detailing ferroptosis. Mitochondria (Mito) generate reactive oxygen species (ROS) that amplify lipid peroxidation, while endosomes (Endo) take part in intracellular iron homeostasis. The two organelles are both involved in the molecular events of ferroptosis. Herein, we developed a polarity-sensitive fluorescent probe (MPY) that targeted Mito and Endo simultaneously. The polarity-triggered emission at 570 nm enables the detection of microenvironmental fluctuation. We observed a general enhancement in Mito polarity during different ferroptosis pathways. Erastin induced the most significant upregulation in Endo polarity and quantity, followed by RSL3 and FIN56, while FINO 2 induced little change. Moreover, the polarity difference between Endo and Mito varied in four ferroptosis stimuli. Accordingly, we revealed that FINO 2 could induce ferritinophagy, judged by the decreased polarity difference between Endo and Mito.