Cardiolipin Promotes Pore-Forming Activity of Alpha-Synuclein Oligomers in Mitochondrial Membranes
Cardiolipin Promotes Pore-Forming Activity of Alpha-Synuclein Oligomers in Mitochondrial Membranes
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DOI：
10.1021/acschemneuro.9b00320
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发表时间：
2019-08-01
影响因子：
5
通讯作者：
Vassallo, Neville
中科院分区：
文献类型：
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作者：
Ghio, Stephanie;Camilleri, Angelique;Vassallo, Neville
形成淀粉样蛋白的α-突触核蛋白（α S）蛋白的聚集与帕金森病（PD）（最常见的运动神经退行性疾病）的病因密切相关。许多研究表明，α S的可溶性聚集中间体（称为低聚物）可透化多种磷脂膜;因此，膜破坏可能是α S毒性的关键致病机制。鉴于线粒体功能障碍在PD中的中心地位，因此，我们探讨了平面脂质双层中α S低聚物形成的离子渗透孔，反映了线粒体膜的复合磷脂组成。使用单通道电生理学，我们记录了不同的多级电导（100-400 pS）与阶梯式电流转换，典型的蛋白质结合的纳米孔，在类膜。重要的是，我们观察到心磷脂（CL）的存在，线粒体膜的标志性磷脂，增强α S-脂质相互作用和α S寡聚体的膜孔形成活性。此外，预孵育分离的线粒体与CL特异性染料保护免受α S寡聚体诱导的线粒体肿胀和细胞色素c的释放。因此，我们倾向于α S寡聚体直接穿孔富含CL的局部脂质环境，例如外部线粒体接触位点或内部线粒体膜，以诱导线粒体功能障碍的情况。因此，α-S孔复合物形成的药理学调节可能会保护线粒体膜的完整性并减轻PD中的线粒体功能障碍。
Aggregation of the amyloid-forming alpha-synuclein (alpha S) protein is closely associated with the etiology of Parkinson's disease (PD), the most common motor neurodegenerative disorder. Many studies have shown that soluble aggregation intermediates of alpha S, termed oligomers, permeabilize a variety of phospholipid membranes; thus, membrane disruption may represent a key pathogenic mechanism of alpha S toxicity. Given the centrality of mitochondrial dysfunction in PD, we therefore probed the formation of ion-permeable pores by alpha S oligomers in planar lipid bilayers reflecting the complex phospholipid composition of mitochondrial membranes. Using single-channel electrophysiology, we recorded distinct multilevel conductances (100-400 pS) with stepwise current transitions, typical of protein-bound nanopores, in mitochondrial-like membranes. Crucially, we observed that the presence of cardiolipin (CL), the signature phospholipid of mitochondria' membranes, enhanced alpha S-lipid interaction and the membrane pore-forming activity of alpha S oligomers. Further, preincubation of isolated mitochondria with a CL-specific dye protected against alpha S oligomer-induced mitochondrial swelling and release of cytochrome c. Hence, we favor a scenario in which alpha S oligomers directly porate a local lipid environment rich in CL, for instance outer mitochondrial contact sites or the inner mitochondrial membrane, to induce mitochondrial dysfunction. Pharmacological modulation of alpha S pore complex formation might thus preserve mitochondrial membrane integrity and alleviate mitochondrial dysfunction in PD.