Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany.
Institute of Metabolism and Cell Death, Helmholtz Center Munich, Neuherberg, Germany.
Mol Metab. 2022 Mar;57:101436. doi: 10.1016/j.molmet.2022.101436. Epub 2022 Jan 6.
Ferroptosis continues to emerge as a novel modality of cell death with important therapeutic implications for a variety of diseases, most notably cancer and degenerative diseases. While susceptibility, initiation, and execution of ferroptosis have been linked to reprogramming of cellular lipid metabolism, imbalances in iron-redox homeostasis, and aberrant mitochondrial respiration, the detailed mechanisms of ferroptosis are still insufficiently well understood.
Here we show that diminished proteasome function is a new mechanistic feature of ferroptosis. The transcription factor nuclear factor erythroid-2, like-1 (NFE2L1) protects from ferroptosis by sustaining proteasomal activity. In cellular systems, loss of NFE2L1 reduced cellular viability after the induction of both chemically and genetically induced ferroptosis, which was linked to the regulation of proteasomal activity under these conditions. Importantly, this was reproduced in a Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) patient-derived cell line carrying mutated glutathione peroxidase-4 (GPX4), a critical regulator of ferroptosis. Also, reduced proteasomal activity was associated with ferroptosis in Gpx4-deficient mice. In a mouse model for genetic Nfe2l1 deficiency, we observed brown adipose tissue (BAT) involution, hyperubiquitination of ferroptosis regulators, including the GPX4 pathway, and other hallmarks of ferroptosis.
Our data highlight the relevance of the NFE2L1-proteasome pathway in ferroptosis. Manipulation of NFE2L1 activity might enhance ferroptosis-inducing cancer therapies as well as protect from aberrant ferroptosis in neurodegeneration, general metabolism, and beyond.
铁死亡作为一种新型细胞死亡方式不断涌现，对多种疾病（尤其是癌症和退行性疾病）具有重要的治疗意义。虽然铁死亡的易感性、起始和执行与细胞脂质代谢的重新编程、铁-氧化还原平衡的失衡以及异常的线粒体呼吸有关，但铁死亡的详细机制仍了解不足。
在这里，我们表明蛋白酶体功能减弱是铁死亡的一个新的机制特征。转录因子核因子红细胞 2 样因子 1（NFE2L1）通过维持蛋白酶体活性来保护细胞免受铁死亡。在细胞系统中，化学和基因诱导铁死亡后，NFE2L1 的缺失降低了细胞活力，这与这些条件下蛋白酶体活性的调节有关。重要的是，这在携带突变谷胱甘肽过氧化物酶 4（GPX4）的 Sedaghatian 型脊椎骨发育不良（SSMD）患者来源细胞系中得到了重现，GPX4 是铁死亡的关键调节因子。此外，在 Gpx4 缺陷小鼠中，蛋白酶体活性的降低与铁死亡有关。在遗传 Nfe2l1 缺乏的小鼠模型中，我们观察到棕色脂肪组织（BAT）萎缩、铁死亡调节因子（包括 GPX4 途径）的泛素化减少以及铁死亡的其他特征。
我们的数据强调了 NFE2L1-蛋白酶体途径在铁死亡中的相关性。NFE2L1 活性的操纵可能增强诱导铁死亡的癌症疗法，并防止神经退行性变、一般代谢等中的异常铁死亡。
