Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP+

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2014
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Zhao, Liang
Kullmann, Cornelius
Förster, Sunniva
Jagtap, Smita
Meiser, Johannes
Leparc, German
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Cell Death & Disease. 2014, 5, e1222. eISSN 2041-4889. Available under: doi: 10.1038/cddis.2014.166
Zusammenfassung

Assessment of the network of toxicity pathways by Omics technologies and bioinformatic data processing paves the road toward a new toxicology for the twenty-first century. Especially, the upstream network of responses, taking place in toxicant-treated cells before a point of no return is reached, is still little explored. We studied the effects of the model neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) by a combined metabolomics (mass spectrometry) and transcriptomics (microarrays and deep sequencing) approach to provide unbiased data on earliest cellular adaptations to stress. Neural precursor cells (LUHMES) were differentiated to homogeneous cultures of fully postmitotic human dopaminergic neurons, and then exposed to the mitochondrial respiratory chain inhibitor MPP+ (5 μM). At 18–24 h after treatment, intracellular ATP and mitochondrial integrity were still close to control levels, but pronounced transcriptome and metabolome changes were seen. Data on altered glucose flux, depletion of phosphocreatine and oxidative stress (e.g., methionine sulfoxide formation) confirmed the validity of the approach. New findings were related to nuclear paraspeckle depletion, as well as an early activation of branches of the transsulfuration pathway to increase glutathione. Bioinformatic analysis of our data identified the transcription factor ATF-4 as an upstream regulator of early responses. Findings on this signaling pathway and on adaptive increases of glutathione production were confirmed biochemically. Metabolic and transcriptional profiling contributed complementary information on multiple primary and secondary changes that contribute to the cellular response to MPP+. Thus, combined ‘Omics’ analysis is a new unbiased approach to unravel earliest metabolic changes, whose balance decides on the final cell fate.

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570 Biowissenschaften, Biologie
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ATF-4, reactive oxygen species, respiratory chain, metabolomics, systems toxicology, transcriptomics
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ISO 690KRUG, Anne K., Simon GUTBIER, Liang ZHAO, Dominik PÖLTL, Cornelius KULLMANN, Violeta IVANOVA-ROHLING, Sunniva FÖRSTER, Smita JAGTAP, Johannes MEISER, German LEPARC, Stefan SCHILDKNECHT, Martina ADAM, Karsten HILLER, Hesso FARHAN, Thomas BRUNNER, Thomas HARTUNG, Agapios SACHINIDIS, Marcel LEIST, 2014. Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP+. In: Cell Death & Disease. 2014, 5, e1222. eISSN 2041-4889. Available under: doi: 10.1038/cddis.2014.166
BibTex
@article{Krug2014Trans-29108,
  year={2014},
  doi={10.1038/cddis.2014.166},
  title={Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP<sup>+</sup>},
  volume={5},
  journal={Cell Death & Disease},
  author={Krug, Anne K. and Gutbier, Simon and Zhao, Liang and Pöltl, Dominik and Kullmann, Cornelius and Ivanova-Rohling, Violeta and Förster, Sunniva and Jagtap, Smita and Meiser, Johannes and Leparc, German and Schildknecht, Stefan and Adam, Martina and Hiller, Karsten and Farhan, Hesso and Brunner, Thomas and Hartung, Thomas and Sachinidis, Agapios and Leist, Marcel},
  note={Article Number: e1222}
}
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