Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1964-1979.e6
JournalMolecular Cell
Volume84
Issue number10
DOIs
StatePublished - May 16 2024
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Keywords

  • AMPK
  • cancer therapy
  • ETC complex I
  • ferroptosis
  • lipid peroxidation
  • LKB1
  • mitochondria

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