CypD deficiency confers neuroprotection against mitochondrial abnormality caused by lead in SH-SY5Y cell,Toxicology Letters

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CypD deficiency confers neuroprotection against mitochondrial abnormality caused by lead in SH-SY5Y cell
Toxicology Letters ( IF 2.9 ) Pub Date : 2020-05-01 , DOI: 10.1016/j.toxlet.2019.12.025
Fang Ye ₁ , Xiaoyi Li ₂ , Yawen Liu ₁ , Anli Jiang ₁ , Xintong Li ₁ , Luoyao Yang ₁ , Wei Chang ₃ , Jing Yuan ₁ , Jun Chen ₁

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Mitochondrial permeability transition (MPT), which is mainly regulated by cyclophilin D (CypD) encoded by ppif gene, is an early event that occurs during mitochondrial stimuli exposure. Lead (Pb) induces MPT and subsequently causes mitochondrial abnormality, followed by events, including oxidative stress and cell death. Here, we generated a ppif-/- SH-SY5Y cell line to determine the role of CypD in Pb-induced mitochondrial abnormality. CypD deficiency significantly blocked mitochondrial permeability transition pore (MPTP) opening and inhibited mitochondrial membrane potential (MMP) collapse, as well as mitochondrial structure damage and fragmentation caused by Pb. Mitochondria fragmentation and MMP collapse, accompanying with Pb-induced downregulation of Glut1 and Glut3 and inactivation of AMPK signaling pathway, could impair the energy supply in wildtype cells. Meanwhile, ppif knockout can alleviate these impairments and maintain the energy supply. In addition, reactive oxygen species accumulation and cell death caused by Pb can also be attenuated by ppif knockout, thereby promoting cell survival. Our study tends to identify CypD as an important contributor to Pb-induced mitochondrial abnormality and provides a potential strategy to inhibit Pb neurotoxicity.

中文翻译：

CypD 缺陷赋予 SH-SY5Y 细胞中铅引起的线粒体异常的神经保护作用

线粒体通透性转变（MPT）主要由 ppif 基因编码的亲环蛋白 D（CypD）调节，是线粒体刺激暴露过程中发生的早期事件。铅 (Pb) 会诱导 MPT，随后导致线粒体异常，进而引发氧化应激和细胞死亡等事件。在这里，我们生成了 ppif-/- SH-SY5Y 细胞系，以确定 CypD 在 Pb 诱导的线粒体异常中的作用。 CypD缺陷显着阻断线粒体通透性转换孔（MPTP）开放并抑制线粒体膜电位（MMP）崩溃，以及Pb引起的线粒体结构损伤和断裂。线粒体碎裂和 MMP 崩溃，伴随着 Pb 诱导的 Glut1 和 Glut3 下调以及 AMPK 信号通路失活，可能会损害野生型细胞的能量供应。同时，ppif敲除可以减轻这些损害并维持能源供应。此外，ppif敲除也可以减弱Pb引起的活性氧积累和细胞死亡，从而促进细胞存活。我们的研究倾向于确定 CypD 是 Pb 诱导的线粒体异常的重要贡献者，并提供了抑制 Pb 神经毒性的潜在策略。

更新日期：2020-05-01

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