Bioenergetics | Rare Diseases | Oxygen | Calcium Uniporter
Mitochondria and Inborn Errors of Energy Metabolism  

Mitochondrial respiratory chain disorders (RCDs) collectively represent the most common inborn errors of metabolism. They are defined by a biochemical defect in the electron transport chain and can impact one or more organ systems, in infancy or in adulthood.  Their diagnosis and management are incredibly challenging, with no proven therapies to date.  Our laboratory has developed “integrative genomics” strategies to discover genes underlying these disorders, in which we combine the power of human genetics with integrative strategies to prioritize and pinpoint causal genes.  Using this approach, we and our collaborators have discovered over 20 Mendelian disease genes.  We are currently applying next-generation genomics and metabolomics methods to understand how these mutations lead to end organ pathology — not only do these studies provide insights into mechanism, they also yield quantitative biomarkers with which to track disease severity.


Selected Publications
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 Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing
Calvo SE, Compton AG, Hershman SG, Lim SC, Lieber DS, Tucker EJ, Laskowski A, Garone C, Liu S, Jaffe DB, Christodoulou J, Fletcher JM, Bruno DL, Goldblatt J, DiMauro S, Thorburn DR, Mootha VK.
Science Translational Medicine: 4(118):118ra10. 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):1571-1575. 2010
arrow Mitochondrial dysfunction remodels one-carbon metabolism in human cells
Bao XR, Ong S, Goldberger O, Peng J, Sharma R, Thompson DA, Vafai SB, Cox AG, Marutani E, Ichinose F, Goessling W, Regev A, Carr SA, Clish CB, Mootha VK.
eLife: 5:e10575. 2016
arrow Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity
Sharma R, Reinstadler, B, Engelstad K, Skinner OS, Stackowitz E, Haller RG, Clish CB, Pierce K, Walker MA, Fryer R, Oglesbee D, Mao X, Shungu DC, Khatri A, Hirano M, De Vivo D, Mootha VK.
The Journal of Clinical Investigation: 131(2):e136055. 2021