Systems Biology | Rare Diseases | Common Diseases | Calcium Uniporter
Systems Approaches to Common Human Disease  

Although we focus on pure mitochondrial biology and orphan mitochondrial disorders, we fully expect our work to have broad implications for many common human diseases. For example, we developed Gene Set Enrichment Analysis (GSEA) to discover that the OXPHOS genes exhibit reduced expression in diabetic muscle. We and our collaborators implemented GSEA into what is now a widely used software package for studying a wide array of human disease and cellular processes. While studying post-transcriptional mechanisms in the regulation of mitochondrial protein expression, we discovered a widespread and unexpected impact of upstream open reading frames (uORFs) in the global control of protein expression - these results may have important implications for linking genomic sequence variation to phenotype. Finally, we have applied metabolic profiling technologies to study orphan mitochondrial disorders, but the technology has been very useful for studying common diseases, such as type 2 diabetes. Recently we used this same technology to discover that rapidly proliferating cancer cells exhibit an increased reliance on the mitochondrial glycine/1-carbon pathway, thereby revealing a potentially new target for chemotherapy.


Selected Publications
arrow PGC-1α responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes
Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstråle M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman BM, Lander ES, Hirschhorn JN, Altshuler D, Groop LC.
Nature Genetics 34(3):267-273. 2003
arrow Gene set enrichment analysis: A knowledge-based approach for Interpreting genomewide expression profiles
Subramanian AS, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP.
Proceedings of the National Academy of Sciences U.S.A., 102:15545-15550. 2005
arrow Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity
Shaham O, Wei R, Wang TJ, Ricciardi C, Lewis GD, Vasan RS, Carr SA, Thadhani R, Gerszten RE, Mootha VK.
Molecular Systems Biology 4:214. 2008
arrow Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans
Calvo SE, Pagliarini DJ, Mootha VK.
Proceedings of the National Academy of Sciences U.S.A. 106(18):7507-7512. 2009
Metabolite profiling reveals a key role for glycine in rapid cancer cell proliferation
Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza A, Kafri R, Kirschner MW, Clish CB, Mootha VK.
Science: 336(6084):1040-1044. 2012