Systems-scale analysis reveals pathways involved in cellular response to methamphetamine

Lijie Sun, Hong Mei Li, Manfredo J. Seufferheld, Kent R. Walters, Venu M. Margam, Amber Jannasch, Naomi Diaz, Catherine P. Riley, Weilin Sun, Yueh Feng Li, William M. Muir, Jun Xie, Jing Wu, Fan Zhang, Jake Y. Chen, Eric L. Barker, Jiri Adamec, Barry R. Pittendrigh

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: Methamphetamine (METH), an abused illicit drug, disrupts many cellular processes, including energy metabolism, spermatogenesis, and maintenance of oxidative status. However, many components of the molecular underpinnings of METH toxicity have yet to be established. Network analyses of integrated proteomic, transcriptomic and metabolomic data are particularly well suited for identifying cellular responses to toxins, such as METH, which might otherwise be obscured by the numerous and dynamic changes that are induced. Methodology/Results: We used network analyses of proteomic and transcriptomic data to evaluate pathways in Drosophila melanogaster that are affected by acute METH toxicity. METH exposure caused changes in the expression of genes involved with energy metabolism, suggesting a Warburg-like effect (aerobic glycolysis), which is normally associated with cancerous cells. Therefore, we tested the hypothesis that carbohydrate metabolism plays an important role in METH toxicity. In agreement with our hypothesis, we observed that increased dietary sugars partially alleviated the toxic effects of METH. Our systems analysis also showed that METH impacted genes and proteins known to be associated with muscular homeostasis/contraction, maintenance of oxidative status, oxidative phosphorylation, spermatogenesis, iron and calcium homeostasis. Our results also provide numerous candidate genes for the METH-induced dysfunction of spermatogenesis, which have not been previously characterized at the molecular level. Conclusion: Our results support our overall hypothesis that METH causes a toxic syndrome that is characterized by the altered carbohydrate metabolism, dysregulation of calcium and iron homeostasis, increased oxidative stress, and disruption of mitochondrial functions.

Original languageEnglish (US)
Article numbere18215
JournalPloS one
Volume6
Issue number4
DOIs
StatePublished - May 2 2011

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Methamphetamine
spermatogenesis
homeostasis
carbohydrate metabolism
transcriptomics
proteomics
energy metabolism
iron
toxicity
calcium
process energy
oxidative phosphorylation
systems analysis
metabolomics
glycolysis
acute toxicity
Spermatogenesis
Drosophila melanogaster
oxidative stress
toxins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Sun, L., Li, H. M., Seufferheld, M. J., Walters, K. R., Margam, V. M., Jannasch, A., ... Pittendrigh, B. R. (2011). Systems-scale analysis reveals pathways involved in cellular response to methamphetamine. PloS one, 6(4), [e18215]. https://doi.org/10.1371/journal.pone.0018215

Systems-scale analysis reveals pathways involved in cellular response to methamphetamine. / Sun, Lijie; Li, Hong Mei; Seufferheld, Manfredo J.; Walters, Kent R.; Margam, Venu M.; Jannasch, Amber; Diaz, Naomi; Riley, Catherine P.; Sun, Weilin; Li, Yueh Feng; Muir, William M.; Xie, Jun; Wu, Jing; Zhang, Fan; Chen, Jake Y.; Barker, Eric L.; Adamec, Jiri; Pittendrigh, Barry R.

In: PloS one, Vol. 6, No. 4, e18215, 02.05.2011.

Research output: Contribution to journalArticle

Sun, L, Li, HM, Seufferheld, MJ, Walters, KR, Margam, VM, Jannasch, A, Diaz, N, Riley, CP, Sun, W, Li, YF, Muir, WM, Xie, J, Wu, J, Zhang, F, Chen, JY, Barker, EL, Adamec, J & Pittendrigh, BR 2011, 'Systems-scale analysis reveals pathways involved in cellular response to methamphetamine', PloS one, vol. 6, no. 4, e18215. https://doi.org/10.1371/journal.pone.0018215
Sun L, Li HM, Seufferheld MJ, Walters KR, Margam VM, Jannasch A et al. Systems-scale analysis reveals pathways involved in cellular response to methamphetamine. PloS one. 2011 May 2;6(4). e18215. https://doi.org/10.1371/journal.pone.0018215
Sun, Lijie ; Li, Hong Mei ; Seufferheld, Manfredo J. ; Walters, Kent R. ; Margam, Venu M. ; Jannasch, Amber ; Diaz, Naomi ; Riley, Catherine P. ; Sun, Weilin ; Li, Yueh Feng ; Muir, William M. ; Xie, Jun ; Wu, Jing ; Zhang, Fan ; Chen, Jake Y. ; Barker, Eric L. ; Adamec, Jiri ; Pittendrigh, Barry R. / Systems-scale analysis reveals pathways involved in cellular response to methamphetamine. In: PloS one. 2011 ; Vol. 6, No. 4.
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abstract = "Background: Methamphetamine (METH), an abused illicit drug, disrupts many cellular processes, including energy metabolism, spermatogenesis, and maintenance of oxidative status. However, many components of the molecular underpinnings of METH toxicity have yet to be established. Network analyses of integrated proteomic, transcriptomic and metabolomic data are particularly well suited for identifying cellular responses to toxins, such as METH, which might otherwise be obscured by the numerous and dynamic changes that are induced. Methodology/Results: We used network analyses of proteomic and transcriptomic data to evaluate pathways in Drosophila melanogaster that are affected by acute METH toxicity. METH exposure caused changes in the expression of genes involved with energy metabolism, suggesting a Warburg-like effect (aerobic glycolysis), which is normally associated with cancerous cells. Therefore, we tested the hypothesis that carbohydrate metabolism plays an important role in METH toxicity. In agreement with our hypothesis, we observed that increased dietary sugars partially alleviated the toxic effects of METH. Our systems analysis also showed that METH impacted genes and proteins known to be associated with muscular homeostasis/contraction, maintenance of oxidative status, oxidative phosphorylation, spermatogenesis, iron and calcium homeostasis. Our results also provide numerous candidate genes for the METH-induced dysfunction of spermatogenesis, which have not been previously characterized at the molecular level. Conclusion: Our results support our overall hypothesis that METH causes a toxic syndrome that is characterized by the altered carbohydrate metabolism, dysregulation of calcium and iron homeostasis, increased oxidative stress, and disruption of mitochondrial functions.",
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AU - Li, Hong Mei

AU - Seufferheld, Manfredo J.

AU - Walters, Kent R.

AU - Margam, Venu M.

AU - Jannasch, Amber

AU - Diaz, Naomi

AU - Riley, Catherine P.

AU - Sun, Weilin

AU - Li, Yueh Feng

AU - Muir, William M.

AU - Xie, Jun

AU - Wu, Jing

AU - Zhang, Fan

AU - Chen, Jake Y.

AU - Barker, Eric L.

AU - Adamec, Jiri

AU - Pittendrigh, Barry R.

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N2 - Background: Methamphetamine (METH), an abused illicit drug, disrupts many cellular processes, including energy metabolism, spermatogenesis, and maintenance of oxidative status. However, many components of the molecular underpinnings of METH toxicity have yet to be established. Network analyses of integrated proteomic, transcriptomic and metabolomic data are particularly well suited for identifying cellular responses to toxins, such as METH, which might otherwise be obscured by the numerous and dynamic changes that are induced. Methodology/Results: We used network analyses of proteomic and transcriptomic data to evaluate pathways in Drosophila melanogaster that are affected by acute METH toxicity. METH exposure caused changes in the expression of genes involved with energy metabolism, suggesting a Warburg-like effect (aerobic glycolysis), which is normally associated with cancerous cells. Therefore, we tested the hypothesis that carbohydrate metabolism plays an important role in METH toxicity. In agreement with our hypothesis, we observed that increased dietary sugars partially alleviated the toxic effects of METH. Our systems analysis also showed that METH impacted genes and proteins known to be associated with muscular homeostasis/contraction, maintenance of oxidative status, oxidative phosphorylation, spermatogenesis, iron and calcium homeostasis. Our results also provide numerous candidate genes for the METH-induced dysfunction of spermatogenesis, which have not been previously characterized at the molecular level. Conclusion: Our results support our overall hypothesis that METH causes a toxic syndrome that is characterized by the altered carbohydrate metabolism, dysregulation of calcium and iron homeostasis, increased oxidative stress, and disruption of mitochondrial functions.

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