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Strittmatter, Laura Anne

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Strittmatter

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Laura Anne

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Strittmatter, Laura Anne

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    Linking Human Genetic Variation to Mitochondrial Metabolism
    (2014-06-06) Strittmatter, Laura Anne; Mootha, Vamsi Krishna; Clardy, Jon; Berry, Gerard; Mazitschek, Ralph
    Genetic variation has a powerful impact on human metabolism and disease. Traditionally, this relationship has either been studied at a high level using top-down descriptive studies of patients with genetically defined inborn errors of metabolism, or else from the bottom up, with molecular biology and biochemical studies of single proteins. Recent advances in genetic sequencing, metabolic profiling technology, and structural biology are rapidly enabling the integration of these approaches towards a more complete description of human metabolism.
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    MICU2, a Paralog of MICU1, Resides within the Mitochondrial Uniporter Complex to Regulate Calcium Handling
    (Public Library of Science, 2013) Plovanich, Molly; Bogorad, Roman L.; Sancak, Yasemin; Kamer, Kimberli; Strittmatter, Laura Anne; Li, Andrew A.; Girgis, Hany S.; Kuchimanchi, Satya; De Groot, Jack; Speciner, Lauren; Taneja, Nathan; OShea, Jonathan; Koteliansky, Victor; Mootha, Vamsi
    Mitochondrial calcium uptake is present in nearly all vertebrate tissues and is believed to be critical in shaping calcium signaling, regulating ATP synthesis and controlling cell death. Calcium uptake occurs through a channel called the uniporter that resides in the inner mitochondrial membrane. Recently, we used comparative genomics to identify MICU1 and MCU as the key regulatory and putative pore-forming subunits of this channel, respectively. Using bioinformatics, we now report that the human genome encodes two additional paralogs of MICU1, which we call MICU2 and MICU3, each of which likely arose by gene duplication and exhibits distinct patterns of organ expression. We demonstrate that MICU1 and MICU2 are expressed in HeLa and HEK293T cells, and provide multiple lines of biochemical evidence that MCU, MICU1 and MICU2 reside within a complex and cross-stabilize each other's protein expression in a cell-type dependent manner. Using in vivo RNAi technology to silence MICU1, MICU2 or both proteins in mouse liver, we observe an additive impairment in calcium handling without adversely impacting mitochondrial respiration or membrane potential. The results identify MICU2 as a new component of the uniporter complex that may contribute to the tissue-specific regulation of this channel.