Our lab combines the new tools of genomics with classic biochemistry and physiology to probe mitochondrial physiology. In recent years, we have comprehensively characterized the organelle's proteome to produce an inventory of 1100 proteins we call MitoCarta. We now use large-scale computational analysis in combination with RNAi to systematically elucidate the function of these 1100 proteins. For example, we have performed a large-scale RNA co-expression analysis to spotlight novel mRNA binding proteins that regulate mtDNA gene expression. We have performed large-scale phylogenetic analysis to identify novel proteins required for the assembly and activity of complex I of the respiratory chain. We have also used comparative proteomics to reveal proteins required for mitochondrial calcium uptake. We are currently combining these approaches with small molecule perturbations and global metabolic profiling.