Proton Tunneling Allows a Proton-Coupled Electron Transfer Process in the Cancer Cell

Area of Science:

• Biochemistry
• Cell Biology
• Photochemistry

Background:

• Proton-coupled electron transfer (PCET) is crucial for activating C-H bonds in biological systems.
• Cancer cells under hypoxia rely on the mitochondrial electron transport chain (ETC) as a key redox regulator.
• Photodynamic therapy (PDT) is a cancer treatment modality that utilizes light to generate reactive oxygen species (ROS).

Purpose of the Study:

• To develop a facile PCET process in cancer cells by modulating proton tunneling.
• To design an alternative PDT that depletes the mitochondrial ETC in hypoxic cancer cells.
• To investigate the effect of PCET on mitochondrial inner membrane potential (MMP) and morphology.

Main Methods:

• Utilized fluorescence lifetime imaging microscopy (FLIM) to monitor MMP changes.
• Irradiated cancer cells for 30 minutes to observe PCET-induced effects.
• Employed photoluminescence experiments and Density Functional Theory (DFT) calculations to understand proton tunneling.

Main Results:

• Observed a shift in mean fluorescence lifetime and a significant drop in signal after irradiation, indicating oxidative stress.
• Demonstrated PCET-induced reorganization of mitochondrial morphology from tubular to vesicle-like structures.
• Confirmed PCET promotes ROS-induced oxidative stress, leading to mitochondrial dysfunction.

Conclusions:

• The developed PCET strategy offers a promising alternative for photodynamic therapy in cancer treatment.
• Modulating proton tunneling in PCET can effectively target and disrupt mitochondrial function in cancer cells.
• This research provides insights into the role of proton tunneling in PCET and its application in cancer therapy.