Institute for Genetics, University of Cologne, Joseph-Stelzmann-Straße 26, 50931, Cologne, Germany.
CECAD Cluster of Excellence, University of Cologne, Joseph-Stelzmann-Straße 26, 50931, Cologne, Germany.
Cell Death Differ. 2021 May;28(5):1644-1657. doi: 10.1038/s41418-020-00691-x. Epub 2020 Dec 17.
Ferroptosis is an iron-dependent form of regulated necrosis associated with lipid peroxidation. Despite its key role in the inflammatory outcome of ferroptosis, little is known about the molecular events leading to the disruption of the plasma membrane during this type of cell death. Here we show that a sustained increase in cytosolic Ca is a hallmark of ferroptosis that precedes complete bursting of the cell. We report that plasma membrane damage leading to ferroptosis is associated with membrane nanopores of a few nanometers in radius and that ferroptosis, but not lipid peroxidation, can be delayed by osmoprotectants. Importantly, Ca fluxes during ferroptosis induce the activation of the ESCRT-III-dependent membrane repair machinery, which counterbalances the kinetics of cell death and modulates the immunological signature of ferroptosis. Our findings with ferroptosis provide a unifying concept that sustained increase of cytosolic Ca prior to plasma membrane rupture is a common feature of regulated types of necrosis and position ESCRT-III activation as a general protective mechanism in these lytic cell death pathways.
铁死亡是一种与脂质过氧化相关的铁依赖性调节性细胞坏死形式。尽管铁死亡在其炎症后果中起着关键作用，但对于导致这种细胞死亡时质膜破裂的分子事件知之甚少。在这里，我们表明，细胞质 Ca2+的持续增加是铁死亡的一个标志，先于细胞完全破裂。我们报告说，导致铁死亡的质膜损伤与半径为几个纳米的膜纳米孔有关，并且铁死亡而不是脂质过氧化可以通过渗透保护剂延迟。重要的是，铁死亡过程中的 Ca2+流诱导了 ESCRT-III 依赖性膜修复机制的激活，该机制平衡了细胞死亡的动力学，并调节了铁死亡的免疫学特征。我们对铁死亡的研究提供了一个统一的概念，即在质膜破裂之前细胞质 Ca2+的持续增加是调节性细胞坏死的共同特征，并将 ESCRT-III 的激活定位为这些裂解性细胞死亡途径中的一般保护机制。
