Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA.
Nat Rev Mol Cell Biol. 2024 Jan;25(1):65-82. doi: 10.1038/s41580-023-00650-7. Epub 2023 Sep 29.
Mitochondria are multifaceted organelles with key roles in anabolic and catabolic metabolism, bioenergetics, cellular signalling and nutrient sensing, and programmed cell death processes. Their diverse functions are enabled by a sophisticated set of protein components encoded by the nuclear and mitochondrial genomes. The extent and complexity of the mitochondrial proteome remained unclear for decades. This began to change 20 years ago when, driven by the emergence of mass spectrometry-based proteomics, the first draft mitochondrial proteomes were established. In the ensuing decades, further technological and computational advances helped to refine these 'maps', with current estimates of the core mammalian mitochondrial proteome ranging from 1,000 to 1,500 proteins. The creation of these compendia provided a systemic view of an organelle previously studied primarily in a reductionist fashion and has accelerated both basic scientific discovery and the diagnosis and treatment of human disease. Yet numerous challenges remain in understanding mitochondrial biology and translating this knowledge into the medical context. In this Roadmap, we propose a path forward for refining the mitochondrial protein map to enhance its discovery and therapeutic potential. We discuss how emerging technologies can assist the detection of new mitochondrial proteins, reveal their patterns of expression across diverse tissues and cell types, and provide key information on proteoforms. We highlight the power of an enhanced map for systematically defining the functions of its members. Finally, we examine the utility of an expanded, functionally annotated mitochondrial proteome in a translational setting for aiding both diagnosis of mitochondrial disease and targeting of mitochondria for treatment.
线粒体是具有多种功能的细胞器，在合成代谢和分解代谢、生物能量学、细胞信号转导和营养感应以及程序性细胞死亡过程中具有关键作用。它们的多种功能是由核基因组和线粒体基因组编码的一组复杂的蛋白质组件实现的。线粒体蛋白质组的范围和复杂性几十年来一直不清楚。这种情况在 20 年前发生了变化，当时，基于质谱的蛋白质组学的出现推动了第一批线粒体蛋白质组草图的建立。在接下来的几十年里，进一步的技术和计算进展帮助完善了这些“图谱”，目前对核心哺乳动物线粒体蛋白质组的估计范围从 1000 到 1500 种蛋白质。这些汇编的创建提供了一个以前主要以还原论方式研究的细胞器的系统视图，并加速了基础科学发现以及人类疾病的诊断和治疗。然而，在理解线粒体生物学并将这些知识转化为医学背景方面仍然存在许多挑战。在本路线图中，我们提出了一个改进线粒体蛋白质图谱的前进道路，以增强其发现和治疗潜力。我们讨论了新兴技术如何帮助检测新的线粒体蛋白质，揭示它们在不同组织和细胞类型中的表达模式，并提供关于蛋白质异构体的关键信息。我们强调了增强图谱的功能，用于系统地定义其成员的功能。最后，我们研究了扩展的、功能注释的线粒体蛋白质组在翻译环境中的效用，以帮助线粒体疾病的诊断和针对线粒体的治疗。
