Mass spectrometry-based stable-isotope tracing uncovers metabolic alterations in pyruvate kinase-deficient Aedes aegypti mosquitoes

Petchampai, Natthida; Isoe, Jun; Horvath, Thomas D.; Dagan, S.; Tan, Lin; Lorenzi, Philip L.; Hawke, David H.; Scaraffia, Patricia Y.

doi:10.1016/j.ibmb.2020.103366

Cited by 5 publications

(5 citation statements)

References 37 publications

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“…Genetic inhibition of PK by RNAi disrupts Glc and ammonia metabolism in mosquito whole body. PK silencing delays several physiological processes and reduces [ 13 C]-metabolite abundance (i.e., G6P, F6P, Pyr, Lac, α-KG, citrate, isocitrate, Ala, Glu, Gln, Pro, and UA) mainly at 6 h after feeding, by decreasing the flux of Glc to glycolysis, PPP, Krebs cycle, and pathways associated with ammonia detoxification [38] (Figure 3). The application of metabolomics with cutting-edge genome-editing technologies [39] can further facilitate the discovery of metabolic interactions and regulators that control multiple metabolic pathways in mosquitoes.…”

Section: Central Carbon (C) Metabolism and Related Pathwaysmentioning

confidence: 99%

Unraveling mosquito metabolism with mass spectrometry-based metabolomics

Horvath

Dagan

Scaraffia

2021

Trends in Parasitology

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Section: Central Carbon (C) Metabolism and Related Pathwaysmentioning

confidence: 99%

Unraveling mosquito metabolism with mass spectrometry-based metabolomics

Horvath

Dagan

Scaraffia

2021

Trends in Parasitology

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“…It was previously reported that blood‐fed A. aegypti females metabolize and excrete excess nitrogen through the combined action of multiple pathways 26,28–30,33–35 . It was also found that glucose catabolism contributes to ammonia detoxification and nitrogen waste disposal in female mosquitoes 36–38 . Although uric acid is the major nitrogen waste that blood‐fed A. aegypti females synthesize and excrete, 26,29,39 mosquitoes have evolutionarily adapted to produce urea through uricolysis 30 and argininolysis, 28,39 which is independent of the urea cycle 30 (Figure 8).…”

Section: Discussionmentioning

confidence: 94%

“…We have previously reported that a delay and/or disruption in BM digestion and excretion caused by silencing genes involved in nitrogen and carbon metabolism led to a reduction of transcript levels of genes encoding enzymes involved in ammonia fixation, assimilation, and excretion pathways, 26,28,29 and a decrease in glucose catabolism in blood‐fed A. aegypti females 37 . Here, ODC gene silencing triggered by RNAi also resulted in a downregulation of several genes involved in nitrogen and carbon metabolism (such as GS, GltS, XDH, and G6PDH) in fat body, midguts, and MTs of blood‐fed ODC‐deficient A. aegypti females at 24 h PBM.…”

Section: Discussionmentioning

confidence: 99%

“…26,[28][29][30][33][34][35] It was also found that glucose catabolism contributes to ammonia detoxification and nitrogen waste disposal in female mosquitoes. [36][37][38] Although uric acid is the major nitrogen waste that blood-fed A. aegypti females synthesize and excrete, 26,29,39 mosquitoes have evolutionarily adapted to produce urea through uricolysis 30 and argininolysis, 28,39 which is independent of the urea cycle 30 (Figure 8). The discovery of a crosstalk regulatory mechanism between uricolysis and argininolysis has contributed to partially revealing the complexity of nitrogen waste metabolism in A. aegypti females.…”

Section: Discussionmentioning

confidence: 99%

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Ornithine decarboxylase deficiency critically impairs nitrogen metabolism and survival in Aedes aegypti mosquitoes

et al. 2022

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Ornithine decarboxylase (ODC; EC 4.1.1.17) catalyzes the conversion of ornithine to putrescine, the rate‐limiting first step for de novo polyamine biosynthesis. Previously, we reported that genetic knockdown of xanthine dehydrogenase 1 (XDH1)—a gene encoding the enzyme involved in the last two steps of uric acid synthesis—causes an increase in ODC transcript levels in fat body of blood‐fed Aedes aegypti mosquitoes, suggesting a crosstalk at molecular level between XDH1 and ODC during nitrogen disposal. To further investigate the role of ODC in nitrogen metabolism, we conducted several biochemical and genetic analyses in sugar‐ and blood‐fed A. aegypti females. Distinct ODC gene and protein expression patterns were observed in mosquito tissues dissected during the first gonotrophic cycle. Both pharmacological and RNA interference‐mediated knockdown of ODC negatively impacted mosquito survival, disrupted nitrogen waste disposal, delayed oviposition onset, and decreased fecundity in vitellogenic blood‐fed females. A lag in the expression of two major digestive serine proteases, a reduction of blood meal digestion in the midgut, and a decrease in vitellogenin yolk protein uptake in ovarian follicles were observed by western blots in ODC‐deficient females. Moreover, genetic silencing of ODC showed a broad transcriptional modulation of genes encoding proteins involved in multiple metabolic pathways in mosquito fat body, midgut, and Malpighian tubules prior to and after blood feeding. All together, these data demonstrate that ODC plays an essential role in mosquito metabolism, and that ODC crosstalks with multiple genes and proteins to prevent deadly nitrogen perturbations in A. aegypti females.

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“…26 Genetic alterations and epigenetic modifications of cancer cells lead to abnormal regulation of cellular metabolic pathways. 27 Our activation of these signaling pathways by lncRNA HULC allowed identification of the role of this lncRNA in several important pathological responses of GBM cells, including migration, invasion and proliferation.…”

Section: Discussionmentioning

confidence: 99%

<p>Quantitative Proteomics Analysis Indicates That Upregulation of lncRNA HULC Promotes Pathogenesis of Glioblastoma Cells</p>

Hu¹,

Ye²,

Li³

et al. 2020

OTT

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Purpose: Glioblastoma (GBM) is an aggressive central nervous system (CNS) cancer and a serious threat to human health. The long noncoding RNA (lncRNA) HULC has been implicated in GBM, but the molecular mechanism is uncertain. This study used quantitative proteomic analysis for global identification of HULC-regulated proteins in glioblastoma cells and identification of potential biomarkers. Materials and Methods: qRT-PCR was used to determine the expression of HULC in U87 cells stably transfected with HULC or an empty vector (control). The CCK-8 assay, transwell assay, and wound-scratch assay were used to measure cell proliferation, invasion, and migration. Quantitative proteomics using Tandem Mass Tag (TMT) labeling, highperformance liquid chromatography (HPLC) fractionation, and liquid chromatographymass spectrometry (LC-MS/MS) analysis were used to identify differentially expressed proteins (DEPs). Screened proteins were validated by parallel reaction monitoring (PRM) and Western blotting. Results: Overexpression of HULC led to increased cell proliferation, invasion, and migration. HULC overexpression also led to significant upregulation of 37 proteins and downregulation of 78 proteins. Bioinformatics analysis indicated these proteins had roles in cellular component, biological process, and molecular function. PRM results of 8 of these proteins (PTK2, TNC, ITGAV, LASP1, MAPK14, ITGA1, GNA13, RRAS) were consistent with the LC-MS/MS and Western blotting results. Conclusion:The results of present study suggest that lncRNA HULC promotes GBM cell proliferation, invasion, and migration by regulating RRAS expression, suggesting that RRAS may be a potential biomarker or therapeutic target for this cancer.

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Mass spectrometry-based stable-isotope tracing uncovers metabolic alterations in pyruvate kinase-deficient Aedes aegypti mosquitoes

Cited by 5 publications

References 37 publications

Unraveling mosquito metabolism with mass spectrometry-based metabolomics

Unraveling mosquito metabolism with mass spectrometry-based metabolomics

Ornithine decarboxylase deficiency critically impairs nitrogen metabolism and survival in Aedes aegypti mosquitoes

<p>Quantitative Proteomics Analysis Indicates That Upregulation of lncRNA HULC Promotes Pathogenesis of Glioblastoma Cells</p>

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