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Mapping the cellular response to electron transport chain inhibitors reveals selective signaling networks triggered by mitochondrial perturbation

Mapping the cellular response to electron transport chain inhibitors reveals selective signaling networks triggered by mitochondrial perturbation

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VAN DER STEL, Wanda, Huan YANG, Nanette G. VRIJENHOEK, Johannes P. SCHIMMING, Giulia CALLEGARO, Giada CARTA, Johannes DELP, Marcel LEIST, Bob VAN DE WATER, Erik H. J. DANEN, 2022. Mapping the cellular response to electron transport chain inhibitors reveals selective signaling networks triggered by mitochondrial perturbation. In: Archives of Toxicology. Springer. 96(1), pp. 259-285. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-021-03160-7

@article{vanderStel2022-01Mappi-55275, title={Mapping the cellular response to electron transport chain inhibitors reveals selective signaling networks triggered by mitochondrial perturbation}, year={2022}, doi={10.1007/s00204-021-03160-7}, number={1}, volume={96}, issn={0340-5761}, journal={Archives of Toxicology}, pages={259--285}, author={van der Stel, Wanda and Yang, Huan and Vrijenhoek, Nanette G. and Schimming, Johannes P. and Callegaro, Giulia and Carta, Giada and Delp, Johannes and Leist, Marcel and van de Water, Bob and Danen, Erik H. J.} }

<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bibo="http://purl.org/ontology/bibo/" xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#" xmlns:foaf="http://xmlns.com/foaf/0.1/" xmlns:void="http://rdfs.org/ns/void#" xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > <rdf:Description rdf:about="https://kops.uni-konstanz.de/rdf/resource/123456789/55275"> <dc:creator>Schimming, Johannes P.</dc:creator> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2021-10-18T13:42:19Z</dcterms:available> <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/55275/1/vanderstel_-2-jolyivyuo4bs1.pdf"/> <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dc:contributor>van de Water, Bob</dc:contributor> <dc:contributor>Callegaro, Giulia</dc:contributor> <dc:creator>Carta, Giada</dc:creator> <dc:language>eng</dc:language> <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/55275"/> <dc:contributor>van der Stel, Wanda</dc:contributor> <dcterms:issued>2022-01</dcterms:issued> <dcterms:title>Mapping the cellular response to electron transport chain inhibitors reveals selective signaling networks triggered by mitochondrial perturbation</dcterms:title> <dc:contributor>Danen, Erik H. J.</dc:contributor> <dcterms:abstract xml:lang="eng">Mitochondrial perturbation is a key event in chemical-induced organ toxicities that is incompletely understood. Here, we studied how electron transport chain (ETC) complex I, II, or III (CI, CII and CIII) inhibitors affect mitochondrial functionality, stress response activation, and cell viability using a combination of high-content imaging and TempO-Seq in HepG2 hepatocyte cells. CI and CIII inhibitors perturbed mitochondrial membrane potential (MMP) and mitochondrial and cellular ATP levels in a concentration- and time-dependent fashion and, under conditions preventing a switch to glycolysis attenuated cell viability, whereas CII inhibitors had no effect. TempO-Seq analysis of changes in mRNA expression pointed to a shared cellular response to CI and CIII inhibition. First, to define specific ETC inhibition responses, a gene set responsive toward ETC inhibition (and not to genotoxic, oxidative, or endoplasmic reticulum stress) was identified using targeted TempO-Seq in HepG2. Silencing of one of these genes, NOS3, exacerbated the impact of CI and CIII inhibitors on cell viability, indicating its functional implication in cellular responses to mitochondrial stress. Then by monitoring dynamic responses to ETC inhibition using a HepG2 GFP reporter panel for different classes of stress response pathways and applying pathway and gene network analysis to TempO-Seq data, we looked for downstream cellular events of ETC inhibition and identified the amino acid response (AAR) as being triggered in HepG2 by ETC inhibition. Through in silico approaches we provide evidence indicating that a similar AAR is associated with exposure to mitochondrial toxicants in primary human hepatocytes. Altogether, we (i) unravel quantitative, time- and concentration-resolved cellular responses to mitochondrial perturbation, (ii) identify a gene set associated with adaptation to exposure to active ETC inhibitors, and (iii) show that ER stress and an AAR accompany ETC inhibition in HepG2 and primary hepatocytes.</dcterms:abstract> <dc:contributor>Yang, Huan</dc:contributor> <dc:contributor>Leist, Marcel</dc:contributor> <dc:contributor>Vrijenhoek, Nanette G.</dc:contributor> <dc:creator>Danen, Erik H. J.</dc:creator> <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/> <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/55275/1/vanderstel_-2-jolyivyuo4bs1.pdf"/> <dcterms:rights rdf:resource="http://creativecommons.org/licenses/by/4.0/"/> <dc:contributor>Schimming, Johannes P.</dc:contributor> <dc:creator>van de Water, Bob</dc:creator> <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <foaf:homepage rdf:resource="http://localhost:8080/jspui"/> <dc:creator>Delp, Johannes</dc:creator> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2021-10-18T13:42:19Z</dc:date> <dc:creator>van der Stel, Wanda</dc:creator> <dc:creator>Vrijenhoek, Nanette G.</dc:creator> <dc:creator>Yang, Huan</dc:creator> <dc:contributor>Carta, Giada</dc:contributor> <dc:contributor>Delp, Johannes</dc:contributor> <dc:creator>Callegaro, Giulia</dc:creator> <dc:rights>Attribution 4.0 International</dc:rights> <dc:creator>Leist, Marcel</dc:creator> </rdf:Description> </rdf:RDF>

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