Unconventional Targeting of a Thiol Peroxidase to the Mitochondrial Intermembrane Space Facilitates Oxidative Protein Folding.
Unconventional Targeting of a Thiol Peroxidase to the Mitochondrial Intermembrane Space Facilitates Oxidative Protein Folding.
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DOI：
10.1016/j.celrep.2017.02.053
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发表时间：
2017-03-14
期刊：
影响因子：
8.8
通讯作者：
Tokatlidis K
中科院分区：
文献类型：
--
作者：
Kritsiligkou P;Chatzi A;Charalampous G;Mironov A Jr;Grant CM;Tokatlidis K
巯基过氧化物酶是一种保守的过氧化氢清除和信号分子，含有氧化还原活性的半胱氨酸残基。我们在这里表明，Gpx 3，在酵母中的主要H2 O2传感器，是存在于线粒体膜间隙（IMS），在那里它提供了一个特定的隔间的作用，在氧化代谢。IMS定位的Gpx 3包含由非AUG密码子编码的18个氨基酸的N-末端延伸形式。这在独立于迄今已知的IMS输入途径的途径中充当线粒体靶向信号。线粒体Gpx 3以氧化还原依赖性方式与Mia 40氧化还原酶相互作用，并促进有效的Mia 40依赖性氧化蛋白折叠。我们发现，缺乏Gpx 3的细胞具有异常的线粒体形态，有缺陷的蛋白质输入能力，和较低的内膜电位，所有这些都可以通过表达Gpx 3的一种单细胞形式来拯救。总之，我们的数据揭示了Gpx 3在线粒体氧化还原调节和蛋白质稳态中的新作用。酵母Gpx 3库通过从非AUG密码子翻译定位于线粒体Gpx 3的缺失导致线粒体结构和膜电位的缺陷Gpx 3与IMS中的氧化蛋白折叠机制相互作用氧化还原传感器蛋白Gpx 3通过从上游非AUG密码子编码的靶向序列导入酵母线粒体。Kritsiligkou等人显示线粒体Gpx 3与氧化蛋白折叠机制协作以确保线粒体蛋白质稳定和形态。
Thiol peroxidases are conserved hydrogen peroxide scavenging and signaling molecules that contain redox-active cysteine residues. We show here that Gpx3, the major H2O2 sensor in yeast, is present in the mitochondrial intermembrane space (IMS), where it serves a compartment-specific role in oxidative metabolism. The IMS-localized Gpx3 contains an 18-amino acid N-terminally extended form encoded from a non-AUG codon. This acts as a mitochondrial targeting signal in a pathway independent of the hitherto known IMS-import pathways. Mitochondrial Gpx3 interacts with the Mia40 oxidoreductase in a redox-dependent manner and promotes efficient Mia40-dependent oxidative protein folding. We show that cells lacking Gpx3 have aberrant mitochondrial morphology, defective protein import capacity, and lower inner membrane potential, all of which can be rescued by expression of a mitochondrial-only form of Gpx3. Together, our data reveal a novel role for Gpx3 in mitochondrial redox regulation and protein homeostasis. A pool of yeast Gpx3 localizes to mitochondria via translation from a non-AUG codon Loss of Gpx3 causes defects in mitochondrial architecture and membrane potential Gpx3 interacts with the oxidative protein folding machinery in the IMS The redox sensor protein Gpx3 is imported into yeast mitochondria via a targeting sequence encoded from an upstream non-AUG codon. Kritsiligkou et al. show that mitochondrial Gpx3 acts in collaboration with the oxidative protein-folding machinery to ensure mitochondrial proteostasis and morphology.