Abstract The mitochondrial intermembrane space (IMS) houses a large spectrum of proteins with distinct and critical functions. Protein import into this mitochondrial sub-compartment is underpinned by an intriguing variety of pathways, many of which are still poorly understood. The constricted volume of the IMS and the topological segregation by the inner membrane cristae into a bulk area surrounded by the boundary inner membrane and the lumen within the cristae is an important factor that adds to the complexity of the protein import, folding and assembly processes. We discuss the main import pathways into the IMS, but also how IMS proteins are degraded or even retro-translocated to the cytosol in an integrated network of interactions that is necessary to maintain a healthy balance of IMS proteins under physiological and cellular stress conditions. We conclude this review by highlighting new and exciting perspectives in this area with a view to develop a better understanding of yet unknown, likely unconventional import pathways, how presequence-less proteins can be targeted and the basis for dual localisation in the IMS and the cytosol. Such knowledge is critical to understanding the dynamic changes of the IMS proteome in response to stress, and particularly important for maintaining optimal mitochondrial fitness.

中文翻译：

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线粒体膜间隙蛋白的生物发生

摘要线粒体膜间隙 (IMS) 容纳了大量具有独特和关键功能的蛋白质。蛋白质输入到这个线粒体亚室的基础是多种有趣的途径，其中许多仍然知之甚少。IMS 的收缩体积和内膜嵴拓扑隔离成被边界内膜和嵴内腔包围的大块区域，是增加蛋白质导入、折叠和组装过程复杂性的重要因素。我们讨论了进入 IMS 的主要输入途径，以及 IMS 蛋白如何在综合相互作用网络中降解甚至逆向易位到细胞质中，这是在生理和细胞压力条件下维持 IMS 蛋白健康平衡所必需的。我们通过强调该领域新的和令人兴奋的观点来结束这篇评论，以期更好地理解未知的、可能非常规的导入途径、如何靶向无前序蛋白以及在 IMS 和细胞质中进行双重定位的基础. 这些知识对于理解 IMS 蛋白质组响应压力的动态变化至关重要，对于维持最佳线粒体健康尤为重要。