Universität zu Köln

Krug, A. K., Gutbier, S., Zhao, L., Poeltl, D., Kullmann, C., Ivanova, V., Foerster, S., Jagtap, S., Meiser, J., Leparc, G., Schildknecht, S., Adam, M., Hiller, K., Farhan, H., Brunner, T., Hartung, T., Sachinidis, A. and Leist, M. (2014). Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP+. Cell Death Dis., 5. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-4889

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Abstract

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 mu M). 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Krug, A. K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gutbier, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhao, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Poeltl, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kullmann, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ivanova, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Foerster, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jagtap, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Meiser, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Leparc, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schildknecht, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Adam, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hiller, K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Farhan, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Brunner, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartung, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachinidis, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Leist, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-439901
DOI:	10.1038/cddis.2014.166
Journal or Publication Title:	Cell Death Dis.
Volume:	5
Date:	2014
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-4889
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CELL-DEATH; PARKINSONS-DISEASE; OXIDATIVE STRESS; DOPAMINERGIC-NEURONS; NEUROBLASTOMA-CELLS; IN-VIVO; INHIBITION; 1-METHYL-4-PHENYLPYRIDINIUM; GLUTATHIONE; GENERATION Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43990