TY - JOUR
T1 - Proton Tunneling Allows a Proton-Coupled Electron Transfer Process in the Cancer Cell
AU - Zhang, Tong
AU - Ghosh, Arindam
AU - Behringer-Pließ, Lisa
AU - Chouhan, Lata
AU - Cunha, Ana V.
AU - Havenith, Remco W.A.
AU - Butkevich, Eugenia
AU - Zhang, Lei
AU - Vázquez, Olalla
AU - Debroye, Elke
AU - Enderlein, Jörg
AU - Das, Shoubhik
N1 - Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society.
PY - 2024/12/10
Y1 - 2024/12/10
N2 - Proton-coupled electron transfer (PCET) is a fundamental redox process and has clear advantages in selectively activating challenging C-H bonds in many biological processes. Intrigued by this activation process, we aimed to develop a facile PCET process in cancer cells by modulating proton tunneling. This approach should lead to the design of an alternative photodynamic therapy (PDT) that depletes the mitochondrial electron transport chain (ETC), the key redox regulator in cancer cells under hypoxia. To observe this depletion process in the cancer cell, we monitored the oxidative-stress-induced depolarization of mitochondrial inner membrane potential (MMP) using fluorescence lifetime imaging microscopy (FLIM). Typically, increasing metabolic stress of cancer cells is reflected in a nontrivial change in the fluorophore’s fluorescence lifetime. After 30 min of irradiation, we observed a shift in the mean lifetime value and a drastic drop in overall fluorescence signal. In addition, our PCET strategy resulted in drastic reorganization of mitochondrial morphology from tubular to vesicle-like and causing an overall depletion of intact mitochondria in the hypodermis of C. elegans. These observations confirmed that PCET promoted ROS-induced oxidative stress. Finally, we gained a clear understanding of the proton tunneling effect in the PCET process through photoluminescence experiments and DFT calculations.
AB - Proton-coupled electron transfer (PCET) is a fundamental redox process and has clear advantages in selectively activating challenging C-H bonds in many biological processes. Intrigued by this activation process, we aimed to develop a facile PCET process in cancer cells by modulating proton tunneling. This approach should lead to the design of an alternative photodynamic therapy (PDT) that depletes the mitochondrial electron transport chain (ETC), the key redox regulator in cancer cells under hypoxia. To observe this depletion process in the cancer cell, we monitored the oxidative-stress-induced depolarization of mitochondrial inner membrane potential (MMP) using fluorescence lifetime imaging microscopy (FLIM). Typically, increasing metabolic stress of cancer cells is reflected in a nontrivial change in the fluorophore’s fluorescence lifetime. After 30 min of irradiation, we observed a shift in the mean lifetime value and a drastic drop in overall fluorescence signal. In addition, our PCET strategy resulted in drastic reorganization of mitochondrial morphology from tubular to vesicle-like and causing an overall depletion of intact mitochondria in the hypodermis of C. elegans. These observations confirmed that PCET promoted ROS-induced oxidative stress. Finally, we gained a clear understanding of the proton tunneling effect in the PCET process through photoluminescence experiments and DFT calculations.
KW - proton tunneling
KW - proton-coupled electron transfer
KW - photodynamic therapy
KW - metal free
KW - fluorenone derivatives
UR - http://www.scopus.com/inward/record.url?scp=85212789611&partnerID=8YFLogxK
U2 - 10.1021/jacsau.4c00815
DO - 10.1021/jacsau.4c00815
M3 - Article
AN - SCOPUS:85212789611
SN - 2691-3704
VL - 4
SP - 4856
EP - 4865
JO - JACS Au
JF - JACS Au
IS - 12
ER -