LRRK2 protects immune cells against erastin-induced ferroptosis
LRRK2 protects immune cells against erastin-induced ferroptosis
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LRRK2保护免疫细胞对抗erastin诱导的铁凋亡
DOI：
10.1016/j.nbd.2022.105917
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发表时间：
2022-11-07
影响因子：
6.1
通讯作者：
Dolga, Amalia M.
中科院分区：
文献类型：
--
作者：
Oun, Asmaa;Soliman, Ahmed;Dolga, Amalia M.
铁死亡是一种铁依赖性调节细胞死亡途径，其特征是过度脂质过氧化。它与许多神经退行性疾病有关，包括帕金森病（PD）。突变和富含亮氨酸重复激酶 2 (LRRK2) 激酶活性的增加与家族性和特发性 PD 病理学相关。与健康个体相比，在携带 LRRK2 突变的 PD 患者的黑质中观察到铁沉积增加，这表明 LRRK2 与铁死亡之间存在潜在联系。然而，LRRK2 在免疫细胞中的作用仍不清楚。本研究旨在探讨 LRRK2 对免疫细胞中铁死亡诱导的细胞死亡的影响。我们使用 LRRK2 亲本 (WT) 和 LRRK2 KO (KO) RAW 264.7 小鼠巨噬细胞。用铁死亡诱导剂erastin 攻击细胞，并使用LRRK2 激酶抑制剂MLi2 研究激酶活性。细胞代谢和活力分析表明，WT 细胞比 KO 细胞更能抵抗铁死亡。 KO 细胞中脂质过氧化和细胞活性氧 (ROS) 生成显着升高。此外，与 WT 细胞相比，erastin 处理后 KO 细胞的线粒体膜电位和线粒体呼吸降低。 LRRK2 激酶功能的抑制导致细胞对erastin 的敏感性增加。与 WT 细胞相比，KO 和激酶抑制的 WT 细胞的细胞和线粒体底物利用率发生了变化。这些结果表明 LRRK2 对 RAW 巨噬细胞中erastin诱导的铁死亡具有保护作用，并指出 LRRK2 激酶功能在保护机制中的重要性。
Ferroptosis is an iron-dependent regulated cell death pathway characterized by excessive lipid peroxidation. It is implicated in many neurodegenerative diseases, including Parkinson's Disease (PD). Mutations and increased leucine-rich repeat kinase 2 (LRRK2) kinase activity are associated with both familial and idiopathic PD pa-thology. Increased iron deposition was observed in the substantia nigra of LRRK2 mutation-carrying PD patients compared to healthy individuals, suggesting a potential link between LRRK2 and ferroptosis. However, the role of LRRK2 in the immune cells is still not well-understood. This study aims to investigate the effect of LRRK2 on ferroptosis-induced cell death in immune cells.We used LRRK2 parental (WT) and LRRK2 KO (KO) RAW 264.7 murine macrophages. Cells were challenged with the ferroptosis inducer, erastin, and the kinase activity was investigated using the LRRK2 kinase inhibitor, MLi2. Cell metabolism and viability analysis showed that WT cells were more resistant to ferroptosis than the KO cells. Lipid peroxidation and cellular reactive oxygen species (ROS) generation were significantly elevated in the KO cells. Furthermore, mitochondrial membrane potential and mitochondrial respiration were decreased in the KO cells after erastin treatment compared to the WT cells. Inhibition of the LRRK2 kinase function resulted in increased cell sensitivity to erastin. Cell and mitochondrial substrates utilization were altered in the KO and kinase inhibited WT cells compared to WT cells. These results indicate a protective role of LRRK2 against erastin-induced ferroptosis in RAW macrophages and point towards the importance of LRRK2 kinase function in the protective mechanism.