Department of Physiology and Pathophysiology, Regenerative Medicine Program and Spinal Cord Research Centre, University of Manitoba, Winnipeg, Canada.
Institute for Metabolism and Cell Death, Helmholtz Zentrum Munchen, Neuherberg, Germany.
Biochim Biophys Acta Mol Cell Res. 2021 Mar;1868(3):118928. doi: 10.1016/j.bbamcr.2020.118928. Epub 2020 Dec 17.
Ferroptosis is a necrotic form of cell death caused by inactivation of the glutathione system and uncontrolled iron-mediated lipid peroxidation. Increasing evidence implicates ferroptosis in a wide range of diseases from neurotrauma to cancer, highlighting the importance of identifying an executioner system that can be exploited for clinical applications. In this study, using pharmacological and genetic models of ferroptosis, we observed that lysosomal membrane permeabilization and cytoplasmic leakage of cathepsin B unleashes structural and functional changes in mitochondria and promotes a not previously reported cleavage of histone H3. Inhibition of cathepsin-B robustly rescued cellular membrane integrity and chromatin degradation. We show that these protective effects are independent of glutathione peroxidase-4 and are mediated by preventing lysosomal membrane damage. This was further confirmed when cathepsin B knockout primary fibroblasts remained unaffected in response to various ferroptosis inducers. Our work identifies new and yet-unrecognized aspects of ferroptosis and identifies cathepsin B as a mediator of ferroptotic cell death.
铁死亡是一种由谷胱甘肽系统失活和不受控制的铁介导的脂质过氧化引起的细胞坏死形式。越来越多的证据表明，铁死亡与从神经创伤到癌症等多种疾病有关，这凸显了确定可用于临床应用的执行系统的重要性。在这项研究中，我们使用铁死亡的药理学和遗传学模型，观察到溶酶体膜通透性增加和组织蛋白酶 B 的细胞质泄漏会引发线粒体的结构和功能变化，并促进以前未报道的组蛋白 H3 切割。组织蛋白酶 B 的抑制可强烈挽救细胞的膜完整性和染色质降解。我们表明，这些保护作用与谷胱甘肽过氧化物酶 4 无关，而是通过防止溶酶体膜损伤来介导的。当各种铁死亡诱导剂对组织蛋白酶 B 敲除原代成纤维细胞没有影响时，这一点得到了进一步证实。我们的工作确定了铁死亡的新的、尚未被认识到的方面，并确定组织蛋白酶 B 是铁死亡细胞死亡的介质。
