Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China; Jiangxi University of Traditional Chinese Medicine, Nanchang, China.
Key Laboratory of Evaluation of Traditional Chinese Medicine Efficacy (Prevention and Treatment of Brain Disease with Mental Disorders); Key Laboratory of Depression Animal Model Based on TCM Syndrome, Jiangxi Administration of Traditional Chinese Medicine; Key Laboratory of TCM for Prevention and Treatment of Brain Diseases with Cognitive Dysfunction, Jiangxi University of Chinese Medicine, Nanchang, China.
Redox Biol. 2023 Jul;63:102760. doi: 10.1016/j.redox.2023.102760. Epub 2023 May 24.
Cancer cells and ischemic diseases exhibit unique metabolic responses and adaptations to energy stress. Forkhead box O 3a (FoxO3a) is a transcription factor that plays an important role in cell metabolism, mitochondrial dysfunction and oxidative stress response. Although the AMP-activated protein kinase (AMPK)/FoxO3a signaling pathway plays a pivotal role in maintaining energy homeostasis under conditions of energy stress, the role of AMPK/FoxO3a signaling in mitochondria-associated ferroptosis has not yet been fully elucidated. We show that glucose starvation induced AMPK/FoxO3a activation and inhibited ferroptosis induced by erastin. Inhibition of AMPK or loss of FoxO3a in cancer cells under the glucose starvation condition can sensitize these cells to ferroptosis. Glucose deprivation inhibited mitochondria-related gene expression, reduced mitochondrial DNA(mtDNA) copy number, decreased expression of mitochondrial proteins and lowered the levels of respiratory complexes by inducing FoxO3a. Loss of FoxO3a promoted mitochondrial membrane potential hyperpolarization, oxygen consumption, lipid peroxide accumulation and abolished the protective effects of energy stress on ferroptosis in vitro. In addition, we identified a FDA-approved antipsychotic agent, the potent FoxO3a agonist trifluoperazine, which largely reduced ferroptosis-associated cerebral ischemia-reperfusion (CIR) injuries in rats through AMPK/FoxO3a/HIF-1α signaling and mitochondria-dependent mechanisms. We found that FoxO3a binds to the promoters of SLC7A11 and reduces CIR-mediated glutamate excitotoxicity through inhibiting the expression of SLC7A11. Collectively, these results suggest that energy stress modulation of AMPK/FoxO3a signaling regulates mitochondrial activity and alters the ferroptosis response. The regulation of FoxO3a by AMPK may play a crucial role in mitochondrial gene expression that controls energy balance and confers resistance to mitochondria-associated ferroptosis and CIR injuries.
癌细胞和缺血性疾病表现出独特的代谢反应和对能量应激的适应。叉头框 O3a（FoxO3a）是一种转录因子，在细胞代谢、线粒体功能障碍和氧化应激反应中发挥重要作用。虽然 AMP 激活的蛋白激酶（AMPK）/FoxO3a 信号通路在能量应激条件下维持能量平衡中起着关键作用，但 AMPK/FoxO3a 信号在与线粒体相关的铁死亡中的作用尚未完全阐明。我们发现葡萄糖饥饿诱导 AMPK/FoxO3a 激活并抑制 erastin 诱导的铁死亡。在葡萄糖饥饿条件下，抑制 AMPK 或丧失 FoxO3a 可使癌细胞对铁死亡敏感。葡萄糖剥夺通过诱导 FoxO3a 抑制与线粒体相关的基因表达，降低线粒体 DNA（mtDNA）拷贝数，减少线粒体蛋白表达，并降低呼吸复合物水平，从而抑制线粒体功能。FoxO3a 的缺失促进线粒体膜电位去极化、耗氧量增加、脂质过氧化物积累，并消除能量应激对铁死亡的保护作用。此外，我们鉴定了一种 FDA 批准的抗精神病药物，强效 FoxO3a 激动剂三氟拉嗪，它通过 AMPK/FoxO3a/HIF-1α 信号和线粒体依赖性机制，在大鼠体内大大减少了与铁死亡相关的脑缺血再灌注（CIR）损伤。我们发现 FoxO3a 结合到 SLC7A11 的启动子上，并通过抑制 SLC7A11 的表达来减少 CIR 介导的谷氨酸兴奋性毒性。总之，这些结果表明，AMPK/FoxO3a 信号的能量应激调节调节线粒体活性并改变铁死亡反应。AMPK 对 FoxO3a 的调节可能在控制能量平衡的线粒体基因表达中发挥关键作用，并赋予对与线粒体相关的铁死亡和 CIR 损伤的抗性。
