The Mysterious Multitude: Structural Perspective on the Accessory Subunits of Respiratory Complex I.
The Mysterious Multitude: Structural Perspective on the Accessory Subunits of Respiratory Complex I.
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DOI：
10.3389/fmolb.2021.798353
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发表时间：
2021
影响因子：
5
通讯作者：
Letts JA
中科院分区：
文献类型：
--
作者：
Padavannil A;Ayala-Hernandez MG;Castellanos-Silva EA;Letts JA
复合物I（Complex I，CI）是线粒体内膜氧化磷酸化电子传递链中最大的蛋白质复合物，并且在电子从还原底物到分子氧的传递中起关键作用。CI由14个跨物种保守的核心亚基和越来越多的从细菌到哺乳动物的辅助亚基组成。添加辅助亚基会导致蛋白质生产和进口的成本，这一事实表明这些亚基起着重要的生理作用。因此，敲除研究已经证明，辅助亚基对于CI组装和功能是必需的。此外，临床研究表明，在辅助亚基的氨基酸取代导致几个衰弱和致命的CI缺陷。然而，CI的辅助亚基的具体作用仍然是神秘的。在这篇综述中，我们探讨了哺乳动物CI的31个辅助亚基的可能作用，通过整合最近的高分辨率CI结构与敲除，组装和临床研究。因此，我们开发了一个框架的实验验证的假设的功能的辅助亚基。我们相信，这一框架将提供对线粒体CI生理学的全面理解的进展，并有助于制定治疗CI缺陷的策略。
Complex I (CI) is the largest protein complex in the mitochondrial oxidative phosphorylation electron transport chain of the inner mitochondrial membrane and plays a key role in the transport of electrons from reduced substrates to molecular oxygen. CI is composed of 14 core subunits that are conserved across species and an increasing number of accessory subunits from bacteria to mammals. The fact that adding accessory subunits incurs costs of protein production and import suggests that these subunits play important physiological roles. Accordingly, knockout studies have demonstrated that accessory subunits are essential for CI assembly and function. Furthermore, clinical studies have shown that amino acid substitutions in accessory subunits lead to several debilitating and fatal CI deficiencies. Nevertheless, the specific roles of CI’s accessory subunits have remained mysterious. In this review, we explore the possible roles of each of mammalian CI’s 31 accessory subunits by integrating recent high-resolution CI structures with knockout, assembly, and clinical studies. Thus, we develop a framework of experimentally testable hypotheses for the function of the accessory subunits. We believe that this framework will provide inroads towards the complete understanding of mitochondrial CI physiology and help to develop strategies for the treatment of CI deficiencies.
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