Mitochondrial Cytochrome c Oxidase Biogenesis Is Regulated by the Redox State of a Heme-Binding Translational Activator.
Mitochondrial Cytochrome c Oxidase Biogenesis Is Regulated by the Redox State of a Heme-Binding Translational Activator.
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DOI：
10.1089/ars.2015.6429
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发表时间：
2016-02
影响因子：
6.6
通讯作者：
Iliana C. Soto;A. Barrientos
中科院分区：
文献类型：
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作者：
Iliana C. Soto;A. Barrientos
目的线粒体细胞色素c氧化酶（考克斯）是呼吸链的最后一个酶，催化氧还原为水，对细胞的功能和存活至关重要。考克斯是一种多聚体复合物，其生物合成受到广泛调控。一种类型的控制靶向细胞色素c氧化酶亚基1（Cox 1），一种在线粒体核糖体上翻译的关键考克斯酶核心亚基。在酿酒酵母中，Cox 1合成和考克斯组装通过负反馈调节环协调。这种协调是由Mss 51介导的，Mss 51是一种血红素敏感的COX 1 mRNA特异性加工因子和翻译激活因子，也是一种COX 1分子伴侣。在这项研究中，我们调查是否Mss 51半化和Mss 51介导的Cox 1合成都调制的还原-氧化（氧化还原）环境。结果我们报道了Cox 1的合成在氧化应激条件下减弱，并确定了潜在的机制之一。我们表明，在体外和体内暴露于过氧化氢诱导形成的二硫键Mss 51涉及CPX基序血红素协调半胱氨酸。mss 51氧化导致血红素配体开关，从而降低血红素结合亲和力并促进其释放。我们证明，除了影响Mss 51依赖血红素传感，氧化应激妥协Mss 51在COX 1 mRNA加工和翻译的作用。创新H2 O2诱导的线粒体翻译下调迄今尚未报道。我们发现，高浓度H2 O2诱导的全球衰减效应，但温和的浓度特别影响COX 1 mRNA的加工和翻译的Mss 51依赖的方式。结论氧化还原环境调节Mss 51的功能，Mss 51在调节考克斯生物合成和有氧能量产生中起重要作用。
AIM Mitochondrial cytochrome c oxidase (COX), the last enzyme of the respiratory chain, catalyzes the reduction of oxygen to water and therefore is essential for cell function and viability. COX is a multimeric complex, whose biogenesis is extensively regulated. One type of control targets cytochrome c oxidase subunit 1 (Cox1), a key COX enzymatic core subunit translated on mitochondrial ribosomes. In Saccharomyces cerevisiae, Cox1 synthesis and COX assembly are coordinated through a negative feedback regulatory loop. This coordination is mediated by Mss51, a heme-sensing COX1 mRNA-specific processing factor and translational activator that is also a Cox1 chaperone. In this study, we investigated whether Mss51 hemylation and Mss51-mediated Cox1 synthesis are both modulated by the reduction-oxidation (redox) environment. RESULTS We report that Cox1 synthesis is attenuated under oxidative stress conditions and have identified one of the underlying mechanisms. We show that in vitro and in vivo exposure to hydrogen peroxide induces the formation of a disulfide bond in Mss51 involving CPX motif heme-coordinating cysteines. Mss51 oxidation results in a heme ligand switch, thereby lowering heme-binding affinity and promoting its release. We demonstrate that in addition to affecting Mss51-dependent heme sensing, oxidative stress compromises Mss51 roles in COX1 mRNA processing and translation. INNOVATION H2O2-induced downregulation of mitochondrial translation has so far not been reported. We show that high H2O2 concentrations induce a global attenuation effect, but milder concentrations specifically affect COX1 mRNA processing and translation in an Mss51-dependent manner. CONCLUSION The redox environment modulates Mss51 functions, which are essential for regulation of COX biogenesis and aerobic energy production.