Faculty, Staff and Student Publications
Publication Date
5-16-2024
Journal
Molecular Cell
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.
Keywords
Animals, Female, Humans, Mice, AMP-Activated Protein Kinase Kinases, AMP-Activated Protein Kinases, Cell Line, Tumor, Electron Transport Complex I, Ferroptosis, Mitochondria, Neoplasms, Phospholipid Hydroperoxide Glutathione Peroxidase, Protein Serine-Threonine Kinases, Signal Transduction, Xenograft Model Antitumor Assays, AMPK, ETC complex I, LKB1, cancer therapy, ferroptosis, lipid peroxidation, mitochondria
DOI
10.1016/j.molcel.2024.04.009
PMID
38759628
PMCID
PMC11104512
PubMedCentral® Posted Date
5-16-2025
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
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