Systems Biology | Rare Diseases | Common Diseases | Calcium Uniporter
Mitochondria and Inborn Errors of Energy Metabolism  

The mitochondrial respiratory chain disorders (RCDs) collectively represent the most common inborn errors of metabolism. They are characterized by a biochemical defect in the electron transport chain. While causal mutations in the mitochondrial genome (mtDNA) have been identified over the past 20 years, recent studies have shown that the majority of RCDs are actually due to mutations in the nuclear genome. Our laboratory has developed “integrative genomics” strategies to discover genes underlying these disorders. For example, we combined evidence from genome-scale profiles of RNA and protein expression to pinpoint LRPPRC as the gene underlying Leigh Syndrome French Canadian Variant (LSFC). Later, we developed a Bayesian approach to integrate eight, genome-scale datasets to spotlight MPV17 as the gene underlying hepatocerebral mtDNA depletion syndrome. In both cases our results have translated into clinical genetic assays that can be used for carrier testing. To date we and our collaborators have discovered over one dozen Mendelian mitochondrial disease genes. We are currently applying next-generation sequencing and metabolomics in translational studies with the goals of discovering the molecular pathophysiology of these disorders and improving their diagnosis and management.

Selected Publications
arrow High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency
Calvo SE, Tucker EJ, Compton AG, Kirby DM, Crawford G, Burtt NP, Rivas M, Guiducci C, Bruno DL, Goldberger O, Redman MC, Wiltshire E, Wilson CJ, Altshuler D, Gabriel SB, Daly MJ, Thorburn DR, Mootha VK.
Nature Genetics, 42(10):851-8. 2010
arrow A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells
Shaham O, Slate NG, Goldberger O, Xu Q, Ramanathan A, Souza AL, Clish CB, Sims KB, Mootha VK.
Proceedings of the National Academy of Sciences U.S.A. 107(4):1571-5. 2010
arrow Mutation of C20orf7 disrupts complex I assembly and causes lethal neonatal mitochondrial disease
Sugiana C, Pagliarini DJ, McKenzie M, Kirby DM, Salemi R, Abu-Amero KK, Dahl HM, Hutchison WM, Vascotto KA, Smith SM, Newbold RF, Christodoulou J, Calvo S, Mootha VK, Ryan MT, Thorburn DR.
American Journal of Human Genetics 83:468-78. 2008
arrow Systematic identification of human mitochondrial disease genes through integrative genomics
Calvo S, Jain M, Xie X , Sheth SA, Goldberger O, Chang B, Spinazzola A, Zeviani M, Carr SA, Mootha VK.
Nature Genetics 38:576-582. 2006
arrow MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion
Spinazzola A, Viscomi C, Fernandez-Vizarra E, Carrara C, D’Adamo P, Calvo S, Marsano RM, Donnini C, Weiher H, Strisciuglio P, Parini R, Sarzi E, Chan A, DiMauro S, Rötig A, Gasparini P, Ferrero I, Mootha VK, Tiranti V, Zeviani M.
Nature Genetics 38:570-575. 2006
arrow Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics
Mootha VK, Lepage P, Miller K, Bunkenborg J, Reich M, Hjerrild M, Delmonte T, Villeneuve A, Sladek R, Zhu F, Mitchell GA, Morin C, Mann M, Hudson TJ, Robinson B, Rioux JD, Lander ES.
Proceedings of the National Academy of Sciences U.S.A., 100(2):  605-610. 2003