Protein Translocation into the Intermembrane Space and Matrix of Mitochondria: Mechanisms and Driving Forces.
Protein Translocation into the Intermembrane Space and Matrix of Mitochondria: Mechanisms and Driving Forces.
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DOI：
10.3389/fmolb.2017.00083
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发表时间：
2017
影响因子：
5
通讯作者：
Herrmann JM
中科院分区：
文献类型：
--
作者：
Backes S;Herrmann JM
线粒体包含两个水亚室，基质和膜间隙（IMS）。基质被线粒体内膜和外膜包围，而IMS夹在两者之间。基质的蛋白质在胞质溶胶中合成为前蛋白，其含有氨基末端基质靶向序列，其通过嵌入外膜和内膜中的易位酶介导其易位。对于这些蛋白质，易位反应由作为内膜易位酶的一部分的输入马达驱动。输入马达利用基质Hsp 70分子和ATP水解将蛋白质棘轮进入线粒体基质。大多数IMS蛋白缺乏前序列，而是利用IMS受体Mia 40，这有助于它们在与蛋白质内二硫键形成偶联的反应中跨外膜易位。这个过程既不需要ATP，也不需要线粒体膜电位。Mia 40扮演两个角色：首先，它充当保持酶，这在IMS蛋白的输入中至关重要，其次，它充当折叠酶，将二硫键引入新输入的蛋白质中，这诱导并稳定它们的天然折叠状态。对于几种Mia 40底物，氧化折叠是它们组装成寡聚复合物的必要先决条件。有趣的是，最近的研究表明，通过使用特定的突变体，Mia 40的两种功能可以在实验上相互分离，从而提供了一种强大的新方法来剖析Mia 40的不同生理作用。在这篇综述中，我们总结了目前的知识与线粒体基质靶向和IMS靶向/Mia 40通路。此外，我们讨论的机械性能，其中线粒体进口电机的一方面和Mia 40的另一方面，驱动器的易位到细胞器中的基板。我们建议，Mia 40在内膜中的横向扩散和氧化介导的传入多肽的折叠支持IMS进口。
Mitochondria contain two aqueous subcompartments, the matrix and the intermembrane space (IMS). The matrix is enclosed by both the inner and outer mitochondrial membranes, whilst the IMS is sandwiched between the two. Proteins of the matrix are synthesized in the cytosol as preproteins, which contain amino-terminal matrix targeting sequences that mediate their translocation through translocases embedded in the outer and inner membrane. For these proteins, the translocation reaction is driven by the import motor which is part of the inner membrane translocase. The import motor employs matrix Hsp70 molecules and ATP hydrolysis to ratchet proteins into the mitochondrial matrix. Most IMS proteins lack presequences and instead utilize the IMS receptor Mia40, which facilitates their translocation across the outer membrane in a reaction that is coupled to the formation of disulfide bonds within the protein. This process requires neither ATP nor the mitochondrial membrane potential. Mia40 fulfills two roles: First, it acts as a holdase, which is crucial in the import of IMS proteins and second, it functions as a foldase, introducing disulfide bonds into newly imported proteins, which induces and stabilizes their natively folded state. For several Mia40 substrates, oxidative folding is an essential prerequisite for their assembly into oligomeric complexes. Interestingly, recent studies have shown that the two functions of Mia40 can be experimentally separated from each other by the use of specific mutants, hence providing a powerful new way to dissect the different physiological roles of Mia40. In this review we summarize the current knowledge relating to the mitochondrial matrix-targeting and the IMS-targeting/Mia40 pathway. Moreover, we discuss the mechanistic properties by which the mitochondrial import motor on the one hand and Mia40 on the other, drive the translocation of their substrates into the organelle. We propose that the lateral diffusion of Mia40 in the inner membrane and the oxidation-mediated folding of incoming polypeptides supports IMS import.
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