Abstract
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.
Highlights
Proteomics and expression profiling have been widely applied to understand the cellular processes [1]
Mitochondria are dynamic organelles that are essential for energy production and cellular processes in eukaryotic cells, and their functional failure is a major cause of ageassociated degenerative diseases
Our results demonstrate that mitochondrial protein repertoires changed to compensate for dysfunctional cellular states by reorganizing mitochondrial protein functional network
Summary
Proteomics and expression profiling have been widely applied to understand the cellular processes [1]. While there are useful information encoded in the list of differentially expressed proteins, identifying the molecular mechanism of cellular processes from the long list of candidate proteins is challenging [3]. Functional module is a group of proteins which are related by one or more cellular and genetic interactions such as co-regulation, co-expression, and the member of a biological pathway or a protein complex [8]. Such module is the building block of cellular organization and carries out unique biological process [9]. Understanding the modular structure of protein functional network should be useful for characterizing the dynamic organization of cellular systems
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