Department of Molecular Medicine, University of Padova, Viale G. Colombo, 3, I-35131, Padova, Italy.
Free Radic Biol Med. 2020 May 20;152:175-185. doi: 10.1016/j.freeradbiomed.2020.02.027. Epub 2020 Mar 9.
Ferroptosis (FPT) is a form of cell death due to missed control of membrane lipid peroxidation (LPO). According to the axiomatic definition of non-accidental cell death, LPO takes place in a scenario of altered homeostasis. FPT, differently from apoptosis, occurs in the absence of any known specific genetically encoded death pathway or specific agonist, and thus must be rated as a regulated, although not "programmed", death pathway. It follows that LPO is under a homeostatic metabolic control and is only permitted when indispensable constraints are satisfied and the antiperoxidant machinery collapses. The activity of the selenoperoxidase Glutathione Peroxidase 4 (GPx4) is the cornerstone of the antiperoxidant defence. Converging evidence on both mechanism of LPO and GPx4 enzymology indicates that LPO is initiated by alkoxyl radicals produced by ferrous iron from the hydroperoxide derivatives of lipids (LOOH), traces of which are the unavoidable drawback of aerobic metabolism. FPT takes place when a threshold has been exceeded. This occurs when the major conditions are satisfied: i) oxygen metabolism leading to the continuous formation of traces of LOOH from phospholipid-containing polyunsaturated fatty acids; ii) missed enzymatic reduction of LOOH; iii) availability of ferrous iron from the labile iron pool. Although the effectors impacting on homeostasis and leading to FPT in physiological conditions are not known, from the available knowledge on LPO and GPx4 enzymology we propose that it is aerobic life itself that, while supporting bioenergetics, is also a critical requisite of FPT. Yet, when the homeostatic control of the steady state between LOOH formation and reduction is lost, LPO is activated and FPT is executed.
铁死亡（Ferroptosis，FPT）是一种由于膜脂质过氧化（Lipid Peroxidation，LPO）失控而导致的细胞死亡形式。根据非意外性细胞死亡的公理定义，LPO 发生在稳态改变的情况下。与细胞凋亡不同，FPT 发生时没有已知的特定遗传编码的死亡途径或特定激动剂，因此必须被归类为一种受调控的、尽管不是“程序化的”死亡途径。因此，LPO 受到稳态代谢的控制，只有在满足必要的约束条件且抗氧化机制崩溃时才会发生。谷胱甘肽过氧化物酶 4（Glutathione Peroxidase 4，GPx4）的硒过氧化物酶活性是抗氧化防御的基石。对 LPO 机制和 GPx4 酶学的综合证据表明，LPO 是由亚铁离子从脂质的过氧化物衍生物（LOOH）产生的烷氧基自由基引发的，LOOH 的痕迹是有氧代谢不可避免的缺点。当达到阈值时，就会发生 FPT。当满足以下主要条件时，就会发生这种情况：i）导致痕量 LOOH 从含有多不饱和脂肪酸的磷脂中连续形成的氧代谢；ii）LOOH 未能被酶还原；iii）从不稳定铁池中获得亚铁离子。虽然在生理条件下影响稳态并导致 FPT 的效应物尚不清楚，但根据我们对 LPO 和 GPx4 酶学的现有知识，我们提出有氧生活本身虽然支持生物能量，但也是 FPT 的关键必要条件。然而，当 LOOH 形成和还原之间的稳态的稳态控制丢失时，LPO 就会被激活，FPT 就会被执行。
