%0 Journal Article
%T Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.
%A Mao C
%A Lei G
%A Horbath A
%A Wang M
%A Lu Z
%A Yan Y
%A Liu X
%A Kondiparthi L
%A Chen X
%A Cheng J
%A Li Q
%A Xu Z
%A Zhuang L
%A Fang B
%A Marszalek JR
%A Poyurovsky MV
%A Olszewski K
%A Gan B
%J Mol Cell
%V 84
%N 10
%D 2024 May 16
%M 38759628
%F 19.328
%R 10.1016/j.molcel.2024.04.009
%X The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes cancer cells to GPX4-inactivation-induced ferroptosis. Furthermore, complex I inhibition synergizes with radiotherapy (RT) to selectively suppress the growth of LKB1-deficient tumors by inducing ferroptosis in mouse models. Our data demonstrate a multifaceted role of complex I in regulating ferroptosis and propose a ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.