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Amyloid β, α-synuclein and the c subunit of the ATP synthase: Can these peptides reveal an amyloidogenic pathway of the permeability transition pore?
Biochimica et Biophysica Acta (BBA) - Biomembranes ( IF 2.8 ) Pub Date : 2020-12-10 , DOI: 10.1016/j.bbamem.2020.183531
Giuseppe F Amodeo 1 , Evgeny V Pavlov 1
Affiliation  

Mitochondrial Permeability Transition (PT) is a phenomenon of increased permeability of the inner mitochondrial membrane in response to high levels of Ca2+ and/or reactive oxygen species (ROS) in the matrix. PT occurs upon the opening of a pore, namely the permeability transition pore (PTP), which dissipates the membrane potential uncoupling the respiratory chain. mPT activation and PTP formation can occur through multiple molecular pathways. The specific focus of this review is to discuss the possible molecular mechanisms of PTP that involve the participation of mitochondrially targeted amyloid peptides Aβ, α-synuclein and c subunit of the ATP synthase (ATPase). As activators of PTP, amyloid peptides are uniquely different from other activators because they are capable of forming channels in lipid bilayers. This property rises the possibility that in this permeabilization pathway the formation of the channel involves the direct participation of peptides, making it uniquely different from other PTP induction mechanisms. In this pathway, a critical step of PTP activation involves the import of amyloidogenic peptides from the cytosol into the matrix. In the matrix these peptides, which would fold into α-helical structure in native conditions, interact with cyclophilin D (CypD) and upon stimulation by elevated ROS and/or the Ca2+ spontaneously misfold into β-sheet ion conducting pores, causing PTP opening.



中文翻译:

淀粉样蛋白β,α-突触核蛋白和ATP合酶的c亚基:这些肽能揭示通透性转换孔的淀粉样蛋白生成途径吗?

线粒体通透性转变(PT)是响应高水平的Ca 2+引起线粒体内膜通透性增加的现象和/或基质中的活性氧(ROS)。PT在孔(即通透性过渡孔(PTP))打开时发生,该孔消散了膜电位,使呼吸链不耦合。mPT激活和PTP形成可以通过多种分子途径发生。本文的重点是讨论PTP可能的分子机制,其中涉及线粒体靶向的淀粉样蛋白肽Aβ,α-突触核蛋白和ATP合酶(ATPase)的c亚基的参与。作为PTP的激活剂,淀粉样蛋白肽与其他激活剂唯一不同,因为它们能够在脂质双层中形成通道。这种特性增加了在通透性途径中通道形成涉及肽直接参与的可能性,使其与其他PTP诱导机制有独特的区别。在这一途径中,PTP活化的关键步骤涉及将淀粉样肽从细胞质中导入到基质中。在基质中,这些肽在自然条件下会折叠成α-螺旋结构,并与亲环蛋白D(CypD)相互作用,并在ROS和/或Ca升高的刺激下相互作用2+自发地错折叠入β-片层离子传导孔中,导致PTP打开。

更新日期:2020-12-23
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