Systems Approaches to Metabolism and Mitochondrial Biology
The research program is aimed at utilizing the new tools of genomics and computational biology to understand mitochondrial biology and metabolism. We are particularly interested in the rare mitochondrial disorders – collectively the largest class of inborn errors of metabolism. Major efforts in the group are aimed at identifying all of the protein components of mitochondria, discovering the regulatory networks that control their expression and assembly, and discovering genetic variants that disrupt these proteins and networks in human disease. Some of our work has implications for type 2 diabetes.
- The mitochondrial calcium uniporter. The mitochondrial calcium uniporter is the primary channel of calcium communication between the cytosol and the mitochondrion. Our laboratory discovered the molecular components of the uniporter, which consists of a pore forming subunit (MCU/MCUb), as well as a calcium-sensing complex (MICU1/2) in the intermembrane space, that are bridged via EMRE. We have now generated knockout mice for several of these components, and ongoing efforts are aimed at determining if these animals exhibit defects in glucose or insulin signaling.
- Alternative carbon assimilation pathways within mitochondria. Our textbooks currently teach us that unlike plants and lower organisms, humans cannot convert fatty acids into sugar, since humans lack a glyoxylate shunt (consisting of an isocitrate lyase and malate synthase, enzymes reportedly not in humans). We recently investigated the function of the protein CLYBL, a never before studied enzyme localized to the mitochondrial matrix. Using a mix of co-expression analysis, co-phylogeny analysis, and structural modeling, we discovered that CLYBL has both malate and beta-methylmalate synthase activities. CLYBL adds to a growing number of enzymes that can utilize glyoxylate, indicating that glyoxylate metabolism may be more widespread in humans than previously expected. Interestingly, 5% of humans harbor a polymorphic premature stop mutation that we have shown is indeed a bona fide loss of function allele. Ongoing work is aimed at determining the physiologic role of a malate synthase in humans.
- Metabolic consequences of benzoic acid, a widely used food preservative. Benzoic acid is a widely used food preservative that is found in soft drinks and other foods. Benzoic acid has long been known to be actively metabolized within mitochondria to produce hippurate. At present, it is not clear if exposure to benzoic acid may have an untoward side effect on glucose and insulin physiology. We have performed a human study in healthy volunteers, who have ingested either water, 75 grams of sugar, in the presence or absence of benzoic acid. We have measured insulin, glucose, and the plasma metabolome (using metabolic profiling) at multiple time points. We are currently analyzing the data, which may have important public health implications.
1. Shaham O, Wei R, Wang TJ, Ricciardi C, Lewis GD, Vasan RS, Carr SA, Thadhani R, Gerszten RE, Mootha VK. Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity, Mol Syst Biol 2008; 4214. PMCID: PMC2538910
2. Perocchi F, Gohil VM, Girgis HS, Bao XR, McCombs JE, Palmer AE, Mootha VK. MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake, Nature 2010; 467(7313):291-6. PMCID: PMC2977980
3. 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. PMCID: PMC3486726
4. Sancak Y, Markhard AL, Kitami T, Kovacs-Bogdan E, Kamer KJ, Udeshi ND, Carr SA, Chaudhuri D, Clapham DE, Li AA, Calvo SE, Goldberger O, Mootha VK. EMRE is an essential component of the mitochondrial calcium uniporter complex, Science 2013; 342(6164):1379-82.
5. Kamer KJ, Mootha VK. MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter. EMBO Rep. 2014;15(3):299-307.