Network Clustering Revealed the Systemic Alterations of Mitochondrial Protein Expression

The mitochondrial protein repertoire varies depending on the cellular state. Protein component modifications caused by mitochondrial DNA (mtDNA) depletion are related to a wide range of human diseases; however, little is known about how nuclear-encoded mitochondrial proteins (mt proteome) changes under such dysfunctional states. In this study, we investigated the systemic alterations of mtDNA-depleted (ρ0) mitochondria by using network analysis of gene expression data. By modularizing the quantified proteomics data into protein functional networks, systemic properties of mitochondrial dysfunction were analyzed. We discovered that up-regulated and down-regulated proteins were organized into two predominant subnetworks that exhibited distinct biological processes. The down-regulated network modules are involved in typical mitochondrial functions, while up-regulated proteins are responsible for mtDNA repair and regulation of mt protein expression and transport. Furthermore, comparisons of proteome and transcriptome data revealed that ρ0 cells attempted to compensate for mtDNA depletion by modulating the coordinated expression/transport of mt proteins. Our results demonstrate that mt protein composition changed to remodel the functional organization of mitochondrial protein networks in response to dysfunctional cellular states. Human mt protein functional networks provide a framework for understanding how cells respond to mitochondrial dysfunctions.

线粒体蛋白质组（mitochondrial protein repertoire）的组成会随细胞状态的改变而发生变化。由线粒体DNA（mitochondrial DNA, mtDNA）缺失引发的蛋白质组分修饰异常，与诸多人类疾病密切相关；然而，目前人们对功能异常状态下核编码线粒体蛋白（nuclear-encoded mitochondrial proteins, mt proteome）的变化规律仍知之甚少。本研究借助基因表达数据的网络分析方法，探究了线粒体DNA缺失（ρ0）线粒体的系统性改变。我们将定量蛋白质组学数据模块化构建为蛋白质功能网络，以此解析线粒体功能异常的系统性特征。研究发现，上调蛋白与下调蛋白分别聚集为两个主要的子网，二者参与的生物学过程存在显著差异。下调蛋白网络模块参与典型的线粒体功能活动，而上调蛋白则负责线粒体DNA修复、线粒体蛋白表达调控与转运过程。此外，对蛋白质组与转录组数据的对比分析显示，ρ0细胞可通过调控线粒体蛋白的协同表达与转运，代偿线粒体DNA缺失造成的损伤。本研究结果表明，细胞在应对功能异常的细胞状态时，线粒体蛋白质组发生改变，从而重塑了线粒体蛋白质网络的功能组织架构。人类线粒体蛋白质功能网络为解析细胞应对线粒体功能异常的机制提供了重要的研究框架。