Gao Minghui, Monian Prashant, Quadri Nosirudeen, Ramasamy Ravichandran, Jiang Xuejun
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Department of Medicine, Langone Medical Center, New York University, 522 1(st) Avenue, New York, NY 10016, USA.
Mol Cell. 2015 Jul 16;59(2):298-308. doi: 10.1016/j.molcel.2015.06.011. Epub 2015 Jul 9.
Ferroptosis has emerged as a new form of regulated necrosis that is implicated in various human diseases. However, the mechanisms of ferroptosis are not well defined. This study reports the discovery of multiple molecular components of ferroptosis and its intimate interplay with cellular metabolism and redox machinery. Nutrient starvation often leads to sporadic apoptosis. Strikingly, we found that upon deprivation of amino acids, a more rapid and potent necrosis process can be induced in a serum-dependent manner, which was subsequently determined to be ferroptosis. Two serum factors, the iron-carrier protein transferrin and amino acid glutamine, were identified as the inducers of ferroptosis. We further found that the cell surface transferrin receptor and the glutamine-fueled intracellular metabolic pathway, glutaminolysis, played crucial roles in the death process. Inhibition of glutaminolysis, the essential component of ferroptosis, can reduce heart injury triggered by ischemia/reperfusion, suggesting a potential therapeutic approach for treating related diseases.
铁死亡已成为一种新的程序性坏死形式，与多种人类疾病有关。然而，铁死亡的机制尚不清楚。本研究报告了铁死亡的多个分子成分的发现及其与细胞代谢和氧化还原机制的密切相互作用。营养饥饿常导致散发性细胞凋亡。令人惊讶的是，我们发现，在缺乏氨基酸的情况下，可通过血清依赖性方式诱导更快速、更有效的坏死过程，随后确定这一过程为铁死亡。两种血清因子，铁载体蛋白转铁蛋白和氨基酸谷氨酰胺，被确定为铁死亡的诱导剂。我们进一步发现，细胞表面转铁蛋白受体和由谷氨酰胺驱动的细胞内代谢途径——谷氨酰胺分解代谢，在死亡过程中起关键作用。抑制谷氨酰胺分解代谢（铁死亡的关键组成部分）可减轻缺血/再灌注引发的心脏损伤，提示了一种治疗相关疾病的潜在治疗方法。
