Professor of Systems Biology and of Medicine
HHMI / Massachusetts General Hospital
Department of Molecular Biology
185 Cambridge Street, CPZN 7250
Boston, MA 02114
Lab Size: Between 20 and 25
Our laboratory focuses on mitochondria. These tiny organelles found in virtually all human cells, serving as the center stage for energy metabolism, ion homeostasis, and apoptosis. Their composition, copy number, and efficiency are dynamic properties, varying across cell types and remodeling during growth and differentiation. Mitochondrial dysfunction underlies rare, inborn errors of metabolism, as well as some of the most common human diseases, such as diabetes, cancer, and neurodegeneration. Given their importance in basic biology and clinical medicine, mitochondria represent an excellent "model" for basic and clinical systems biology.
Our group is broadly interested in characterizing the structure and dynamic properties of mitochondria, understanding how genetic variation influence mitochondrial physiology, and exploiting the network properties of the organelle to design therapies for human disease. To achieve these goals, we combine classic biochemistry and physiology with the new tools of genomics, proteomics, and chemical biology. In recent years, we have used mass spectrometry, microscopy, and computation to define the mitochondrial proteome (an inventory we call MitoCarta). We have subsequently coupled MitoCarta with human genetics to discover over one dozen Mendelian disease genes. We have used computational and comparative genomics in combination with CRISPR screens to predict and validate the function of proteins comprising the mitochondrial calcium uniporter.
Current areas of focus include: (1) nuclear:mitochondrial cross-talk in the control of mitochondrial biogenesis, (2) membrane biochemistry and biophysics of ion and metabolite transport, (3) next-gen sequencing and functional studies of human mitochondrial disease, (4) metabolomics approaches to mitochondrial function, and (5) chemical biology approaches to modulating mitochondrial copy number and function.
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. A mitochondrial protein compendium elucidates complex I disease biology. Cell 2008; 134(1):112-23.
Perocchi F, Gohil VM, Girgis H, Bao R, McCombs J, Palmer A, Mootha VK. MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake. Nature 2010; 467(7313):291-6. PMCID: PMC2977980
Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, Bao XR, Strittmatter L, Goldberger O, Bogorad RL, Koteliansky V, Mootha VK. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter, Nature 2011: 476(7360):341-5. P
Bick AG, Calvo SE, Mootha VK. Evolutionary diversity of the mitochondrial calcium uniporter, Science 2012: 336(6083):86.
Jain IH, Zazzeron L, Goli R, Alexa K, Schatzman-Bone S, Dhillon H, Goldberger O, Peng J, Shalem O, Sanjana NE, Zhang F, Goessling W, Zapol WM, Mootha VK. (2016)
Hypoxia as a therapy for mitochondrial disease Science: 352(6281):54-61