Abstract
Mitochondria carry out specialized functions; compartmentalized, yet integrated into the metabolic and signaling processes of the cell. Although many mitochondrial proteins have been identified, understanding their functional interrelationships has been a challenge. Here we construct a comprehensive network of the mitochondrial system. We integrated genome-wide datasets to generate an accurate and inclusive mitochondrial parts list. Together with benchmarked measures of protein interactions, a network of mitochondria was constructed in their cellular context, including extra-mitochondrial proteins. This network also integrates data from different organisms to expand the known mitochondrial biology beyond the information in the existing databases. Our network brings together annotated and predicted functions into a single framework. This enabled, for the entire system, a survey of mutant phenotypes, gene regulation, evolution, and disease susceptibility. Furthermore, we experimentally validated the localization of several candidate proteins and derived novel functional contexts for hundreds of uncharacterized proteins. Our network thus advances the understanding of the mitochondrial system in yeast and identifies properties of genes underlying human mitochondrial disorders.
Highlights
Mitochondria play a central role in metabolism, energy production, ion homeostasis, and apoptosis [1,2] and are found in most eukaryotes
During evolution most of the genes encoded by the mitochondrial genome were transferred to the nucleus or were lost [7]; only eight proteins are encoded by the mitochondrial DNA (mtDNA) of yeast and 13 in humans
Evaluation of Functional Modules We expected our module map, which focuses on a specific sub-cellular system, to be more accurate than public databases that provide annotation at the genome level
Summary
Mitochondria play a central role in metabolism, energy production, ion homeostasis, and apoptosis [1,2] and are found in most eukaryotes. Genome-scale approaches have catalyzed the identification of mitochondrial proteins in different organisms through, for example, analysis of deletion phenotypes [8,9], subcellular localization [10,11,12], gene expression [4,13,14,15], and mass spectrometry-based proteomics [4,16,17,18,19,20,21].
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