A major, long-term goal of our laboratory is to achieve a holistic understanding of all mitochondrial circuitry and how it is regulated.  An early milestone in our laboratory was the full molecular characterization of the mammalian mitochondrial proteome (called MitoCarta).  To systematically define the function of these 1100 proteins, we have developed new computational approaches and combined them with large-scale genetic and biochemical approaches.  For example, we have developed “big data” co-expression (CLIC) and co-phylogeny (CLIME) tools with which to predict the function of these proteins, revealing key protein components of mitochondrial mRNA processing, complex I assembly, as well as dicarboxylate metabolism.  We have also applied targeted and genome-wide CRISPR screens to systematically identify human genes required for mitochondrial oxidative phosphorylation.  Finally, we have developed genetically encoded tools — LbNOX, TPNOX, LOXCAT — with which to manipulate NADH/NAD+, NADPH/NADP+, and lactate/pyruvate ratios — to begin to understand the logic of redox compartmentalization within and between human cells.