Assessing Systems Properties of Yeast Mitochondria through an Interaction Map of the Organelle

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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. Mitochondria are organelles which are best known as the cell's energy powerhouses. They have a special evolutionary origin derived from bacteria engulfed about 2 billion years ago by eukaryotes. Surprisingly, mitochondrial functions have been retained over evolution, so that unicellular yeast and multicellular organisms like humans share many of the same mitochondrial components. Here the authors complemented previous efforts to identify the “parts” of the mitochondrial system, but as for any system, this is not enough to understand how it works. By integrating information on protein localization, function, and interaction, the authors go a step further and propose a map of the mitochondrial organelle and its surroundings. This map suggests the involvement of hundreds of so far uncharacterized proteins in mitochondrial function. By taking advantage of the high conservation of the organelle to humans, the authors investigate properties of human genes involved in mitochondrial diseases. They find that the disease genes have ancient origin and a mild mutant phenotype when their function is abolished in yeast. The approach applied here can be extended to other organelles or organisms and illustrates a growing trend in understanding biological processes in their whole rather than in isolated parts.