The Disulfide Relay System of Mitochondria Is Required for the Biogenesis of Mitochondrial Ccs1 and Sod1
The Disulfide Relay System of Mitochondria Is Required for the Biogenesis of Mitochondrial Ccs1 and Sod1
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DOI：
10.1016/j.jmb.2008.10.088
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发表时间：
2009-01-16
影响因子：
5.6
通讯作者：
Hell, Kai
中科院分区：
文献类型：
--
作者：
Reddehase, Silvia;Grumbt, Barbara;Hell, Kai
细胞保护自己免受氧应激和活性氧物种的伤害。这一过程中的一个重要酶是超氧化物歧化酶SOD1，它能将超氧阴离子自由基转化为水和过氧化氢。SOD1的生物发生依赖于其铜伴侣Ccs1，Ccs1在SOD1中引入了一个二硫键和一个铜离子。Ccs1和SOD1存在于细胞质中，但也存在于线粒体的膜间间隙(IMS)，即线粒体外膜和内膜之间的间隙。Ccs1.介导Sod1的线粒体定位。在这里，我们报道了Ccs1组分的生物发生。和SOD1存在于酿酒酵母的线粒体中。线粒体的IMS含有一个由输入受体Mia40和硫醇氧化酶Erv1组成的二硫键中继系统，该系统驱动半胱氨酸残基以典型的双Cx(3)C和双Cx(9)C基序排列的底物的输入。我们发现，Mia40的缺失会导致Ccs1和SOD1水平的下降。另一方面，Mia40的过度表达增加了这两种蛋白的线粒体比例。此外，增加MIa40的水平提高了Ccs1的进口率，而在MIa40耗尽时则降低了进口率。Mia40与Ccs1形成混合二硫键，提示Mia40在Ccs1中产生二硫键起作用。我们认为，二硫键传递系统通过Mia40将二硫键转移到Ccs1，然后Ccs1将二硫键穿梭到SOD1。综上所述，二硫化物传递系统对Ccs1的输入起着至关重要的作用，从而影响SOD1的转运，并控制Ccs1和SOD1在线粒体IMS和胞浆之间的分布。(C)2008爱思唯尔有限公司。保留所有权利。
Cells protect themselves against oxygen stress and reactive oxygen species. An important enzyme in this process is superoxide dismutase, Sod1, which converts superoxide radicals into water and hydrogen peroxide. The biogenesis of functional Sod1 is dependent on its copper chaperone, Ccs1, which introduces a disulfide bond and a copper ion into Sod1. Ccs1 and Sod1 are present in the cytosol but are also found in the mitochondrial intermembrane space (IMS), the compartment between the outer and the inner membrane of mitochondria. Ccs1. mediates mitochondrial localization of Sod1.Here, we report on the biogenesis of the fractions of Ccs1. and Sod1 present in mitochondria of Saccharomyces cerevisiae. The IMS of mitochondria, harbors a disulfide relay system consisting of the import receptor Mia40 and the thiol oxidase Erv1, which drives the import of substrates with conserved cysteine residues arranged in typical twin Cx(3)C and twin Cx(9)C motifs. We show that depletion of Mia40 results in decreased levels of Ccs1 and Sod1. On the other hand, overexpression of Mia40 increased the mitochondrial fraction of both proteins. In addition, the import rates of Ccs1 were enhanced by increased levels of Mia40 and reduced upon depletion of Mia40. Mia40 forms mixed disulfides with Ccs1, suggesting a role of Mia40 for the generation of disulfide bonds in Ccs1. We suggest that the disulfide relay system transfers disulfide bonds via Mia40 to Ccs1, which then shuttles disulfide bonds to Sod1. In conclusion, the disulfide relay system is crucial for the import of Ccs1, thereby affecting the transport of Sod1, and it can control the distribution of Ccs1 and Sod1 between the IMS of mitochondria and the cytosol. (C) 2008 Elsevier Ltd. All rights reserved.