Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for...

Area of Science:

• Biochemistry
• Cell Biology
• Cancer Research

Background:

• The mitochondrial electron transport chain (ETC) plays a complex role in cellular processes.
• Ferroptosis, a regulated form of cell death, is implicated in various diseases, including cancer.
• The precise mechanisms by which ETC components influence ferroptosis remain incompletely understood.

Purpose of the Study:

• To investigate the role of mitochondrial ETC complex I in regulating ferroptosis.
• To explore the therapeutic potential of targeting complex I in cancer treatment, particularly in LKB1-deficient tumors.

Main Methods:

• Pharmacological inhibition and genetic ablation of ETC complex I.
• Assessment of ubiquinol and ATP levels.
• Activation of AMP-activated protein kinase (AMPK).
• Evaluation of ferroptosis induction by glutathione peroxidase 4 (GPX4) inhibition.
• In vivo studies using mouse models of LKB1-deficient tumors.
• Combination therapy with radiotherapy (RT).

Main Results:

• Complex I inhibition reduces ubiquinol and ATP levels, activating AMPK.
• AMPK activation has a suppressive effect on ferroptosis.
• Inhibition of complex I in LKB1-AMPK-inactivated cells or cells with genetic ablation of complex I sensitizes cancer cells to GPX4 inhibition-induced ferroptosis.
• Complex I inhibition synergizes with radiotherapy to induce ferroptosis and suppress tumor growth in LKB1-deficient mouse models.

Conclusions:

• Mitochondrial ETC complex I has a multifaceted role in ferroptosis regulation.
• Targeting complex I can overcome resistance to ferroptosis in LKB1-deficient cancers.
• Complex I inhibition combined with radiotherapy presents a promising ferroptosis-inducing therapeutic strategy for LKB1-deficient tumors.