PDF(Pubmed)
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.
摘要：
线粒体电子传递链（ETC）在调节铁死亡中的作用尚未完全阐明。这里,我们发现，ETC复合物I的药理学抑制降低泛醇水平，同时降低ATP水平并激活AMP激活的蛋白激酶（AMPK），这两种效应以其在促进和抑制铁性凋亡中的作用而闻名，分别。因此,复合物I抑制剂对谷胱甘肽过氧化物酶4（GPX4）抑制诱导的铁凋亡的影响有限。复合物I在LKB1-AMPK灭活细胞中的药理学抑制作用，或复合物I的遗传消融（不会触发明显的AMPK激活），消除AMPK介导的铁凋亡抑制作用，并使癌细胞对GPX4失活诱导的铁凋亡敏感。此外，复合物I抑制与放射疗法（RT）协同作用，通过在小鼠模型中诱导铁凋亡来选择性抑制LKB1缺陷型肿瘤的生长。我们的数据证明了复合物I在调节铁凋亡中的多方面作用，并提出了针对LKB1缺陷型癌症的铁凋亡诱导治疗策略。
