Cardiolipin externalization mediates prion protein (PrP) peptide 106-126-associated mitophagy and mitochondrial dysfunction.
Cardiolipin externalization mediates prion protein (PrP) peptide 106-126-associated mitophagy and mitochondrial dysfunction.
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DOI：
10.3389/fnmol.2023.1163981
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发表时间：
2023
影响因子：
4.8
通讯作者：
Yang, Lifeng
中科院分区：
文献类型：
--
作者：
Yang, Dongming;Li, Jie;Li, Zhiping;Zhao, Mengyang;Wang, Dongdong;Sun, Zhixin;Wen, Pei;Gou, Fengting;Dai, Yuexin;Ji, Yilan;Li, Wen;Zhao, Deming;Yang, Lifeng
适当的线粒体功能对于维持正常的神经元功能以防止神经退行性疾病的发展至关重要。受损线粒体的持续积累在朊病毒病的发病机制中发挥着重要作用，该发病机制涉及一系列事件，最终导致活性氧的产生和神经元死亡。我们之前的研究表明，PrP106−126 诱导的 PINK1/Parkin 介导的线粒体自噬是有缺陷的，并导致 PrP106−126 处理后受损线粒体的积累。据报道，外化心磷脂 (CL) 是一种线粒体特异性磷脂，通过与线粒体外膜上的 LC3II 直接相互作用，在线粒体自噬中发挥作用。 CL 外化在 PrP106−126 诱导的线粒体自噬中的参与及其在用 PrP106−126 处理的 N2a 细胞的其他生理过程中的意义仍然未知。我们证明 PrP106−126 肽在 N2a 细胞中引起线粒体自噬的时间过程，该过程逐渐增加，随后减少。 CL 外化到线粒体表面也有类似的趋势，导致细胞水平上的 CL 含量逐渐减少。通过敲低 CL 合成酶（负责 CL 的从头合成）或磷脂扰乱酶-3 和 NDPK-D（负责 CL 易位到线粒体表面）来抑制 CL 外化，显着减少 N2a 细胞中 PrP106−126 诱导的线粒体自噬。同时，抑制 CL 重新分布显着减少 PrP106−126 治疗中 PINK1 和 DRP1 的募集，但 Parkin 募集没有显着减少。此外，CL外化的抑制导致氧化磷酸化受损和严重的氧化应激，从而导致线粒体功能障碍。我们的结果表明，PrP106−126 在 N2a 细胞上诱导的 CL 外化在线粒体自噬的启动中发挥积极作用，从而导致线粒体功能的稳定。
Proper mitochondrial performance is imperative for the maintenance of normal neuronal function to prevent the development of neurodegenerative diseases. Persistent accumulation of damaged mitochondria plays a role in prion disease pathogenesis, which involves a chain of events that culminate in the generation of reactive oxygen species and neuronal death. Our previous studies have demonstrated that PINK1/Parkin-mediated mitophagy induced by PrP106−126 is defective and leads to an accumulation of damaged mitochondria after PrP106−126 treatment. Externalized cardiolipin (CL), a mitochondria-specific phospholipid, has been reported to play a role in mitophagy by directly interacting with LC3II at the outer mitochondrial membrane. The involvement of CL externalization in PrP106−126-induced mitophagy and its significance in other physiological processes of N2a cells treated with PrP106−126 remain unknown. We demonstrate that the PrP106−126 peptide caused a temporal course of mitophagy in N2a cells, which gradually increased and subsequently decreased. A similar trend in CL externalization to the mitochondrial surface was seen, resulting in a gradual decrease in CL content at the cellular level. Inhibition of CL externalization by knockdown of CL synthase, responsible for de novo synthesis of CL, or phospholipid scramblase-3 and NDPK-D, responsible for CL translocation to the mitochondrial surface, significantly decreased PrP106−126-induced mitophagy in N2a cells. Meanwhile, the inhibition of CL redistribution significantly decreased PINK1 and DRP1 recruitment in PrP106−126 treatment but had no significant decrease in Parkin recruitment. Furthermore, the inhibition of CL externalization resulted in impaired oxidative phosphorylation and severe oxidative stress, which led to mitochondrial dysfunction. Our results indicate that CL externalization induced by PrP106−126 on N2a cells plays a positive role in the initiation of mitophagy, leading to the stabilization of mitochondrial function.
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