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Li, Andrew A.

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Li

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Andrew A.

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Li, Andrew A.
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    A Systems-Level Investigation of the Genetic and Phenotypic Heterogeneity of Mitochondrial Disorders
    (2016-05-17) Li, Andrew A.
    Mitochondrial diseases are a diverse set of phenotypically and genetically heterogeneous disorders. This thesis explores these two themes using a systems approach. One chapter focuses on phenotypic heterogeneity and tissue-specificity by combining existing cancer cell line sequencing and expression data with a pharmacologic screen. Through this approach, we prioritized genes involved in mitochondrial biogenesis and the AKT signaling pathway with sensitivity or resistance to mitochondrial dysfunction. Another chapter investigates a potential complex genetic basis for disease in patients with mitochondrial disorders lacking a molecular diagnosis. We applied existing biological knowledge about protein complexes and metabolic pathways to identify sets of variants in multiple genes that could combine to cause disease, spotlighting Complex I of the respiratory chain and enzymes involved in fatty acid beta-oxidation. Understanding the phenotypic and genetic heterogeneity of diseases is a question that extends beyond the mitochondrial disorders; we hope that these approaches can also be applied to other conditions to characterize the complex interactions underlying human pathophysiology.
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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.