Unraveling ETC Complex I Function in Ferroptosis Reveals a Potential Ferroptosis-inducing Therapeutic Strategy for LKB1-deficient Cancers

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2024 May 17

PMID 38759628

Authors

Chao Mao

Guang Lei

Amber Horbath

Min Wang

Zhengze Lu

Yuelong Yan

Xiaoguang Liu

Lavanya Kondiparthi

Xiong Chen

Jun Cheng

Qidong Li

Zhihao Xu

Li Zhuang

Bingliang Fang

Joseph R Marszalek

Masha V Poyurovsky

Kellen Olszewski

Boyi Gan

Affiliations

Soon will be listed here.

Abstract

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.

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