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Spinelli, Jessica

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Spinelli

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Jessica

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Spinelli, Jessica

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2017 - 20183

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Author's Publications: search.filters.isAuthorOfPublication.7bd7f111-a775-4dc7-a9e7-272310712840

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Now showing 1 - 3 of 3
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    An LC-MS Approach to Quantitative Measurement of Ammonia Isotopologues
    (Nature Publishing Group UK, 2017) Spinelli, Jessica; Kelley, Liam; Haigis, Marcia
    Ammonia is a fundamental aspect of metabolism spanning all of phylogeny. Metabolomics, including metabolic tracing studies, are an integral part of elucidating the role of ammonia in these systems. However, current methods for measurement of ammonia are spectrophotometric, and cannot distinguish isotopologues of ammonia, significantly limiting metabolic tracing studies. Here, we describe a novel LC-MS-based method that quantitatively assesses both 14N-and 15N-isotopologues of ammonia in polar metabolite extracts. This assay (1) quantitatively measures the concentration of ammonia in polar metabolite isolates used for metabolomic studies, and (2) accurately determines the percent isotope abundance of 15N-ammonia in a cell lysate for 15N-isotope tracing studies. We apply this assay to quantitatively measure glutamine-derived ammonia in lung cancer cell lines with differential expression of glutaminase.
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    Strength in numbers: Phosphofructokinase polymerization prevails in the liver
    (The Rockefeller University Press, 2017) Zaganjor, Elma; Spinelli, Jessica; Haigis, Marcia
    Numerous metabolic enzymes assemble into filamentous structures, which are thought to serve additional regulatory functions. In this issue, Webb et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201701084) show that the liver-specific isoform of phosphofructokinase-1 forms filaments in vitro and localizes as puncta in cells along the plasma membrane. This suggests spatial organization of glycolysis in higher organisms.
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    Small-Molecule Screen Identifies De Novo Nucleotide Synthesis as a Vulnerability of Cells Lacking SIRT3
    (2018) Gonzalez Herrera, Karina; Zaganjor, Elma; Ishikawa, Yoshinori; Spinelli, Jessica; Yoon, Haejin; Lin, Jia-Ren; Satterstrom, F. Kyle; Ringel, Alison; Mulei, Stacy; Souza, Amanda; Gorham, Joshua; Benson, Craig C.; Seidman, Jonathan; Sorger, Peter; Clish, Clary B.; Haigis, Marcia
    Summary Sirtuin 3 (SIRT3) is a NAD+-dependent deacetylase downregulated in aging and age-associated diseases such as cancer and neurodegeneration and in high-fat diet (HFD)-induced metabolic disorders. Here, we performed a small-molecule screen and identified an unexpected metabolic vulnerability associated with SIRT3 loss. Azaserine, a glutamine analog, was the top compound that inhibited growth and proliferation of cells lacking SIRT3. Using stable isotope tracing of glutamine, we observed its increased incorporation into de novo nucleotide synthesis in SIRT3 knockout (KO) cells. Furthermore, we found that SIRT3 KO cells upregulated the diversion of glutamine into de novo nucleotide synthesis through hyperactive mTORC1 signaling. Overexpression of SIRT3 suppressed mTORC1 and growth in vivo in a xenograft tumor model of breast cancer. Thus, we have uncovered a metabolic vulnerability of cells with SIRT3 loss by using an unbiased small-molecule screen.