Proton Tunneling\nAllows a Proton-Coupled Electron\nTransfer Process in the Cancer Cell

Proton-coupled electron transfer (PCET) is a fundamental\nredox\nprocess and has clear advantages in selectively activating challenging\nC–H bonds in many biological processes. Intrigued by this activation\nprocess, we aimed to develop a facile PCET process in cancer cells\nby modulating proton tunneling. This approach should lead to the design\nof an alternative photodynamic therapy (PDT) that depletes the mitochondrial\nelectron transport chain (ETC), the key redox regulator in cancer\ncells under hypoxia. To observe this depletion process in the cancer\ncell, we monitored the oxidative-stress-induced depolarization of\nmitochondrial inner membrane potential (MMP) using fluorescence lifetime\nimaging microscopy (FLIM). Typically, increasing metabolic stress\nof cancer cells is reflected in a nontrivial change in the fluorophore’s\nfluorescence lifetime. After 30 min of irradiation, we observed a\nshift in the mean lifetime value and a drastic drop in overall fluorescence\nsignal. In addition, our PCET strategy resulted in drastic reorganization\nof mitochondrial morphology from tubular to vesicle-like and causing\nan overall depletion of intact mitochondria in the hypodermis of C. elegans. These observations confirmed that PCET\npromoted ROS-induced oxidative stress. Finally, we gained a clear\nunderstanding of the proton tunneling effect in the PCET process through\nphotoluminescence experiments and DFT calculations.