Abstract

This paper presents new structural data about mitochondria using correlative light and electron microscopy (CLEM) and cryo-electron tomography. These state-of-the-art structural biology methods allow studying biological objects at nanometer scales under natural conditions. Non-invasiveness of these methods makes them comparable to observing animals in their natural environment on a safari. The paper highlights two areas of research that can only be accomplished using these methods. The study visualized location of the Aβ42 amyloid aggregates in relation to mitochondria to test a hypothesis of development of mitochondrial dysfunction in Alzheimer’s disease. The results showed that the Aβ42 aggregates do not interact with mitochondria, although some of them are closely located. Therefore, the study demonstrated that mitochondrial dysfunction is not directly associated with the effects of aggregates on mitochondrial structure. Other processes should be considered as sources of mitochondrial dysfunction. Second unique area presented in this work is high-resolution visualization of the mitochondrial membranes and proteins in them. Analysis of the cryo-ET data reveals toroidal holes in the lamellar structures of cardiac mitochondrial cristae, where ATP synthases are located. The study proposes a new mechanism for sorting and clustering protein complexes in the membrane based on topology. According to this suggestion, position of the OXPHOS system proteins in the membrane is determined by its curvature. High-resolution tomography expands and complements existing ideas about the structural and functional organization of mitochondria. This makes it possible to study the previously inaccessible structural interactions of proteins with each other and with membranes in vivo.

中文翻译：

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使用电子枪进行狩猎：自然环境中线粒体中蛋白质和膜相互作用的可视化

摘要

本文利用相关光电子显微镜 (CLEM) 和冷冻电子断层扫描技术提供了有关线粒体的新结构数据。这些最先进的结构生物学方法允许在自然条件下研究纳米尺度的生物物体。这些方法的非侵入性使得它们可以与在野生动物园中观察自然环境中的动物相媲美。该论文强调了只能使用这些方法才能完成的两个研究领域。该研究可视化了 Aβ42 淀粉样蛋白聚集体与线粒体的关系，以检验阿尔茨海默病中线粒体功能障碍的假设。结果表明，Aβ42 聚集体不与线粒体相互作用，尽管其中一些聚集体位置很近。因此，研究表明线粒体功能障碍与聚集体对线粒体结构的影响并不直接相关。其他过程应被视为线粒体功能障碍的根源。这项工作中提出的第二个独特领域是线粒体膜及其中蛋白质的高分辨率可视化。对冷冻 ET 数据的分析揭示了心脏线粒体嵴层状结构中的环形孔，ATP 合酶就位于其中。该研究提出了一种基于拓扑结构对膜中蛋白质复合物进行分类和聚类的新机制。根据该建议，膜中 OXPHOS 系统蛋白的位置由其曲率决定。高分辨率断层扫描扩展并补充了有关线粒体结构和功能组织的现有想法。这使得研究蛋白质之间以及体内蛋白质与膜之间以前无法达到的结构相互作用成为可能。