Bioenergetics | Rare Diseases | Oxygen | Calcium Uniporter
Mitochondrial Systems Biology and Bioenergetics  

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.


Selected Publications
arrow A mitochondrial protein compendium elucidates complex I disease biology
Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong SE, Walford GA, Sugiana C, Boneh A, Chen WK, Hill DE, Vidal M, Evans JG, Thorburn DR, Carr SA, Mootha VK.
Cell: 134:112-123. 2008
arrow Expansion of biological pathways based on evolutionary inference
Li Y, Calvo SE, Gutman R, Liu JS, Mootha VK.
Cell: 158(1):213-225. 2014
arrow Complementation of mitochondrial electron transport chain by manipulation of the NAD+/NADH ratio
Titov DV, Cracan V, Goodman RP, Peng J, Grabarek Z, Mootha VK.
Science: 352(6282):231-235. 2016
arrow A genome-wide CRISPR death screen identifies genes essential for oxidative phosphorylation
Arroyo JD, Jourdain AA, Calvo SE, Ballarano CA, Doench JG, Root DE, Mootha VK.
Cell Metabolism: 24(6): 875-885. 2016
arrow CLIC, a tool for expanding biological pathways based on co-expression across thousands of datasets
Li Y, Jourdain AA, Calvo SE, Liu JS, Mootha VK.
PLOS Computational Biology: e1005653. 2017
arrow A genetically encoded tool for manipulation of NADP+/NADPH in living cells
Cracan V, Titov DV, Shen H, Grabarek Z, Mootha VK.
Nature Chemical Biology: 13(10):1088-1095. 2017
arrow An engineered enzyme that targets circulating lactate to alleviate intracellular NADH:NAD+ imbalance
Patgiri A, Skinner OS, Miyazaki Y, Schleifer G, Marutani E, Shah H, Sharma R, Goodman RP, To TL, Bao XR, Ichinose F, Zapol WM, Mootha VK.
Nature Biotechnology: 38: 309-313. 2020