Dept. of Molecular Medicine, University of Padova, V.le G. Colombo, 3, I-35121, Padova, Italy; CRIBI Biotechnology Center, University of Padova, V.le G. Colombo, 3, I-35121, Padova, Italy.
Dept. of Molecular Medicine, University of Padova, V.le G. Colombo, 3, I-35121, Padova, Italy.
Redox Biol. 2020 Jan;28:101328. doi: 10.1016/j.redox.2019.101328. Epub 2019 Sep 20.
Ferroptosis is a form of cell death primed by iron and lipid hydroperoxides and prevented by GPx4. Ferrostatin-1 (fer-1) inhibits ferroptosis much more efficiently than phenolic antioxidants. Previous studies on the antioxidant efficiency of fer-1 adopted kinetic tests where a diazo compound generates the hydroperoxyl radical scavenged by the antioxidant. However, this reaction, accounting for a chain breaking effect, is only minimally useful for the description of the inhibition of ferrous iron and lipid hydroperoxide dependent peroxidation. Scavenging lipid hydroperoxyl radicals, indeed, generates lipid hydroperoxides from which ferrous iron initiates a new peroxidative chain reaction. We show that when fer-1 inhibits peroxidation, initiated by iron and traces of lipid hydroperoxides in liposomes, the pattern of oxidized species produced from traces of pre-existing hydroperoxides is practically identical to that observed following exhaustive peroxidation in the absence of the antioxidant. This supported the notion that the anti-ferroptotic activity of fer-1 is actually due to the scavenging of initiating alkoxyl radicals produced, together with other rearrangement products, by ferrous iron from lipid hydroperoxides. Notably, fer-1 is not consumed while inhibiting iron dependent lipid peroxidation. The emerging concept is that it is ferrous iron itself that reduces fer-1 radical. This was supported by electroanalytical evidence that fer-1 forms a complex with iron and further confirmed in cells by fluorescence of calcein, indicating a decrease of labile iron in the presence of fer-1. The notion of such as pseudo-catalytic cycle of the ferrostatin-iron complex was also investigated by means of quantum mechanics calculations, which confirmed the reduction of an alkoxyl radical model by fer-1 and the reduction of fer-1 radical by ferrous iron. In summary, GPx4 and fer-1 in the presence of ferrous iron, produces, by distinct mechanism, the most relevant anti-ferroptotic effect, i.e the disappearance of initiating lipid hydroperoxides.
铁死亡是一种由铁和脂质过氧化物引发、由 GPx4 预防的细胞死亡形式。Ferrostatin-1（Fer-1）比酚类抗氧化剂更有效地抑制铁死亡。以前关于 Fer-1 的抗氧化效率的研究采用了动力学测试，其中一个重氮化合物产生抗氧化剂清除的过氧自由基。然而，这种反应，代表一个链断裂效应，对于描述亚铁离子和脂质过氧化物依赖性过氧化作用的抑制作用只有最小的用处。清除脂质过氧自由基实际上会从其中生成亚铁离子引发新的过氧自由基链式反应的脂质过氧自由基。我们表明，当 Fer-1 抑制由铁和脂质过氧化物的痕量引发的过氧化作用时，从预先存在的过氧化物痕量产生的氧化物种的模式实际上与在没有抗氧化剂的情况下进行的彻底过氧化作用后观察到的模式相同。这支持了 Fer-1 的抗铁死亡活性实际上是由于其从脂质过氧化物中清除亚铁离子引发的烷氧自由基的观点，以及其他重排产物。值得注意的是，Fer-1 在抑制铁依赖性脂质过氧化作用时不会被消耗。新兴的概念是，亚铁离子本身还原 Fer-1 自由基。这得到了电分析证据的支持，即 Fer-1 与铁形成复合物，并在细胞中通过钙荧光素的荧光进一步证实，表明在 Fer-1 存在下不稳定铁的减少。还通过量子力学计算研究了 Fer-1-铁复合物的这种类似假催化循环的概念，该计算证实了 Fer-1 还原烷氧自由基模型和亚铁离子还原 Fer-1 自由基的模型。总之，在亚铁离子存在下的 GPx4 和 Fer-1 通过不同的机制产生最相关的抗铁死亡效应，即起始脂质过氧化物的消失。
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