Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Biological Sciences, Columbia University, New York, NY, USA.
Nat Cell Biol. 2020 Feb;22(2):225-234. doi: 10.1038/s41556-020-0461-8. Epub 2020 Feb 6.
Energy stress depletes ATP and induces cell death. Here we identify an unexpected inhibitory role of energy stress on ferroptosis, a form of regulated cell death induced by iron-dependent lipid peroxidation. We found that ferroptotic cell death and lipid peroxidation can be inhibited by treatments that induce or mimic energy stress. Inactivation of AMP-activated protein kinase (AMPK), a sensor of cellular energy status, largely abolishes the protective effects of energy stress on ferroptosis in vitro and on ferroptosis-associated renal ischaemia-reperfusion injury in vivo. Cancer cells with high basal AMPK activation are resistant to ferroptosis and AMPK inactivation sensitizes these cells to ferroptosis. Functional and lipidomic analyses further link AMPK regulation of ferroptosis to AMPK-mediated phosphorylation of acetyl-CoA carboxylase and polyunsaturated fatty acid biosynthesis. Our study demonstrates that energy stress inhibits ferroptosis partly through AMPK and reveals an unexpected coupling between ferroptosis and AMPK-mediated energy-stress signalling.
能量应激会消耗 ATP 并诱导细胞死亡。在这里，我们发现了能量应激对铁依赖性脂质过氧化诱导的细胞死亡形式——铁死亡的一种意外抑制作用。我们发现，诱导或模拟能量应激的处理可以抑制铁死亡细胞死亡和脂质过氧化。细胞能量状态的传感器 AMP 激活蛋白激酶 (AMPK) 的失活在很大程度上消除了能量应激对体外铁死亡和体内铁死亡相关肾缺血再灌注损伤的保护作用。基础 AMPK 激活水平较高的癌细胞对铁死亡有抗性，而 AMPK 失活则使这些细胞对铁死亡敏感。功能和脂质组学分析进一步将 AMPK 对铁死亡的调节与 AMPK 介导的乙酰辅酶 A 羧化酶磷酸化和多不饱和脂肪酸生物合成联系起来。我们的研究表明，能量应激通过 AMPK 抑制铁死亡，并揭示了铁死亡和 AMPK 介导的能量应激信号之间的意外偶联。
