Aly Khaled A, Moutaoufik Mohamed Taha, Phanse Sadhna, Zhang Qingzhou, Babu Mohan
Department of Biochemistry, University of Regina, Regina, SK, Canada.
iScience. 2021 Jan 6;24(2):102030. doi: 10.1016/j.isci.2020.102030. eCollection 2021 Feb 19.
Mitochondrial (mt) dysfunction is linked to rare diseases (RDs) such as respiratory chain complex (RCC) deficiency, MELAS, and ARSACS. Yet, how altered mt protein networks contribute to these ailments remains understudied. In this perspective article, we identified 21 mt proteins from public repositories that associate with RCC deficiency, MELAS, or ARSACS, engaging in a relatively small number of protein-protein interactions (PPIs), underscoring the need for advanced proteomic and interactomic platforms to uncover the complete scope of mt connectivity to RDs. Accordingly, we discuss innovative untargeted label-free proteomics in identifying RD-specific mt or other macromolecular assemblies and mapping of protein networks in complex tissue, organoid, and stem cell-differentiated neurons. Furthermore, tag- and label-based proteomics, genealogical proteomics, and combinatorial affinity purification-mass spectrometry, along with advancements in detecting and integrating transient PPIs with single-cell proteomics and transcriptomics, collectively offer seminal follow-ups to enrich for RD-relevant networks, with implications in RD precision medicine.
线粒体（mt）功能障碍与诸如呼吸链复合物（RCC）缺乏症、线粒体脑肌病伴乳酸血症和卒中样发作（MELAS）以及遗传性痉挛性共济失调（ARSACS）等罕见疾病（RDs）相关联。然而，线粒体蛋白质网络的改变如何导致这些疾病仍未得到充分研究。在这篇观点文章中，我们从公共数据库中鉴定出21种与RCC缺乏症、MELAS或ARSACS相关的线粒体蛋白，它们参与的蛋白质 - 蛋白质相互作用（PPI）数量相对较少，这突出了需要先进的蛋白质组学和相互作用组学平台来揭示线粒体与罕见疾病之间完整的联系范围。因此，我们讨论了创新的非靶向无标记蛋白质组学在识别罕见疾病特异性线粒体或其他大分子组装体以及绘制复杂组织、类器官和干细胞分化神经元中的蛋白质网络方面的应用。此外，基于标签和标记的蛋白质组学、谱系蛋白质组学以及组合亲和纯化 - 质谱分析，连同在将瞬时PPI与单细胞蛋白质组学和转录组学进行检测和整合方面的进展，共同为丰富与罕见疾病相关的网络提供了重要的后续研究方向，对罕见疾病精准医学具有重要意义。
