Kritsiligkou Paraskevi, Chatzi Afroditi, Charalampous Georgia, Mironov Aleksandr, Grant Chris M, Tokatlidis Kostas
Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK.
Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
Cell Rep. 2017 Mar 14;18(11):2729-2741. doi: 10.1016/j.celrep.2017.02.053.
Thiol peroxidases are conserved hydrogen peroxide scavenging and signaling molecules that contain redox-active cysteine residues. We show here that Gpx3, the major HO 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.
硫醇过氧化物酶是保守的过氧化氢清除和信号分子，含有氧化还原活性半胱氨酸残基。我们在此表明，酵母中的主要HO传感器Gpx3存在于线粒体外膜间隙（IMS）中，它在氧化代谢中发挥特定于该区域的作用。定位于IMS的Gpx3包含由非AUG密码子编码的18个氨基酸的N末端延伸形式。这在一条独立于迄今已知的IMS导入途径的通路中充当线粒体靶向信号。线粒体Gpx3以氧化还原依赖性方式与Mia40氧化还原酶相互作用，并促进高效的Mia40依赖性氧化蛋白折叠。我们表明，缺乏Gpx3的细胞具有异常的线粒体形态、有缺陷的蛋白质导入能力和较低的内膜电位，所有这些都可以通过仅在线粒体中表达Gpx3来挽救。总之，我们的数据揭示了Gpx3在线粒体氧化还原调节和蛋白质稳态中的新作用。
