Development of a neurotoxicity assay that is tuned to detect mitochondrial toxicants.
Carbohydrate Metabolism
Culture Media
Electron Transport
/ drug effects
Electron Transport Complex I
/ antagonists & inhibitors
Galactose
/ metabolism
Glucose
/ metabolism
Humans
Mitochondria
/ drug effects
Mitochondrial Diseases
/ chemically induced
Neural Stem Cells
/ drug effects
Neurites
/ drug effects
Neurotoxicity Syndromes
/ diagnosis
Toxicity Tests
/ methods
Uncoupling Agents
/ toxicity
High content imaging
High-throughput toxicity screening
Mechanistic safety assessment
Metabolic reprogramming
Mitotoxicity
Neurotoxicity
Journal
Archives of toxicology
ISSN: 1432-0738
Titre abrégé: Arch Toxicol
Pays: Germany
ID NLM: 0417615
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
05
03
2019
accepted:
07
05
2019
pubmed:
14
6
2019
medline:
22
7
2020
entrez:
14
6
2019
Statut:
ppublish
Résumé
Many neurotoxicants affect energy metabolism in man, but currently available test methods may still fail to predict mito- and neurotoxicity. We addressed this issue using LUHMES cells, i.e., human neuronal precursors that easily differentiate into mature neurons. Within the NeuriTox assay, they have been used to screen for neurotoxicants. Our new approach is based on culturing the cells in either glucose or galactose (Glc-Gal-NeuriTox) as the main carbohydrate source during toxicity testing. Using this Glc-Gal-NeuriTox assay, 52 mitochondrial and non-mitochondrial toxicants were tested. The panel of chemicals comprised 11 inhibitors of mitochondrial respiratory chain complex I (cI), 4 inhibitors of cII, 8 of cIII, and 2 of cIV; 8 toxicants were included as they are assumed to be mitochondrial uncouplers. In galactose, cells became more dependent on mitochondrial function, which made them 2-3 orders of magnitude more sensitive to various mitotoxicants. Moreover, galactose enhanced the specific neurotoxicity (destruction of neurites) compared to a general cytotoxicity (plasma membrane lysis) of the toxicants. The Glc-Gal-NeuriTox assay worked particularly well for inhibitors of cI and cIII, while the toxicity of uncouplers and non-mitochondrial toxicants did not differ significantly upon glucose ↔ galactose exchange. As a secondary assay, we developed a method to quantify the inhibition of all mitochondrial respiratory chain functions/complexes in LUHMES cells. The combination of the Glc-Gal-NeuriTox neurotoxicity screening assay with the mechanistic follow up of target site identification allowed both, a more sensitive detection of neurotoxicants and a sharper definition of the mode of action of mitochondrial toxicants.
Identifiants
pubmed: 31190196
doi: 10.1007/s00204-019-02473-y
pii: 10.1007/s00204-019-02473-y
doi:
Substances chimiques
Culture Media
0
Uncoupling Agents
0
Electron Transport Complex I
EC 7.1.1.2
Glucose
IY9XDZ35W2
Galactose
X2RN3Q8DNE
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1585-1608Subventions
Organisme : Bundesministerium für Bildung und Forschung
ID : e:ToP program
Pays : International
Organisme : H2020 European Research Council
ID : EC681002
Pays : International
Organisme : Deutsche Forschungsgemeinschaft
ID : RTG1331
Pays : International
Organisme : Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg
ID : INVITE
Pays : International
Références
Aleo MD, Luo Y, Swiss R, Bonin PD, Potter DM, Will Y (2014) Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump. Hepatology (Baltimore, MD) 60(3):1015–1022. https://doi.org/10.1002/hep.27206
doi: 10.1002/hep.27206
Arroyo JD, Jourdain AA, Calvo SE et al (2016) A Genome-wide CRISPR death screen identifies genes essential for oxidative phosphorylation. Cell Metab 24(6):875–885. https://doi.org/10.1016/j.cmet.2016.08.017
doi: 10.1016/j.cmet.2016.08.017
pubmed: 27667664
pmcid: 5474757
Attene-Ramos MS, Huang R, Michael S et al (2015) Profiling of the Tox21 chemical collection for mitochondrial function to identify compounds that acutely decrease mitochondrial membrane potential. Environ Health Perspect 123(1):49–56. https://doi.org/10.1289/ehp.1408642
doi: 10.1289/ehp.1408642
pubmed: 25302578
Bal-Price A, Crofton KM, Leist M et al (2015a) International STakeholder NETwork (ISTNET): creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes. Arch Toxicol 89(2):269–287. https://doi.org/10.1007/s00204-015-1464-2
doi: 10.1007/s00204-015-1464-2
pubmed: 25618548
pmcid: 4309915
Bal-Price A, Crofton KM, Sachana M et al (2015b) Putative adverse outcome pathways relevant to neurotoxicity. Crit Rev Toxicol 45(1):83–91. https://doi.org/10.3109/10408444.2014.981331
doi: 10.3109/10408444.2014.981331
pubmed: 25605028
pmcid: 5072123
Bal-Price A, Leist M, Schildknecht S, Tschudi-Monnet F, Paini A, Terron A (2018) Adverse outcome pathway on inhibition of the mitochondrial complex I of nigro-striatal neurons leading to parkinsonian motor deficits. OECD Publishing, Paris. https://doi.org/10.1787/b46c3c00-en
doi: 10.1787/b46c3c00-en
Barbosa DJ, Capela JP, de Lourdes Bastos M, Carvalho F (2015) In vitro models for neurotoxicology research. Toxicol Res 4(4):801–842. https://doi.org/10.1039/C4TX00043A
doi: 10.1039/C4TX00043A
Becker WF, Von Jagow G, Anke T, Steglich W (1981) Oudemansin, strobilurin A, strobilurin B and myxothiazol: new inhibitors of the bc 1 segment of the respiratory chain with an E-β-methoxyacrylate system as common structural element. FEBS Lett 132(2):329–333. https://doi.org/10.1016/0014-5793(81)81190-8
doi: 10.1016/0014-5793(81)81190-8
pubmed: 6271595
Begriche K, Massart J, Robin MA, Borgne-Sanchez A, Fromenty B (2011) Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver. J Hepatol 54(4):773–794. https://doi.org/10.1016/j.jhep.2010.11.006
doi: 10.1016/j.jhep.2010.11.006
pubmed: 21145849
Blomme EA, Will Y (2016) Toxicology strategies for drug discovery: present and future. Chem Res Toxicol 29(4):473–504. https://doi.org/10.1021/acs.chemrestox.5b00407
doi: 10.1021/acs.chemrestox.5b00407
pubmed: 26588328
Budnitz DS, Pollock DA, Weidenbach KN, Mendelsohn AB, Schroeder TJ, Annest JL (2006) National surveillance of emergency department visits for outpatient adverse drug events. JAMA 296(15):1858–1866. https://doi.org/10.1001/jama.296.15.1858
doi: 10.1001/jama.296.15.1858
pubmed: 17047216
Daniele RP, Holian SK (1976) A potassium ionophore (valinomycin) inhibits lymphocyte proliferation by its effects on the cell membrane. Proc Natl Acad Sci 73(10):3599–3602. https://doi.org/10.1073/pnas.73.10.3599
doi: 10.1073/pnas.73.10.3599
pubmed: 1068473
de Souza-Fagundes EM, Delp J, Prazeres PDM et al (2018) Correlation of structural features of novel 1,2,3-triazoles with their neurotoxic and tumoricidal properties. Chem Biol Interact 291:253–263. https://doi.org/10.1016/j.cbi.2018.06.029
doi: 10.1016/j.cbi.2018.06.029
pubmed: 29944877
Delp J, Gutbier S, Cerff M et al (2018a) Stage-specific metabolic features of differentiating neurons: implications for toxicant sensitivity. Toxicol Appl Pharmacol 354:64–80. https://doi.org/10.1016/j.taap.2017.12.013
doi: 10.1016/j.taap.2017.12.013
pubmed: 29278688
Delp J, Gutbier S, Klima S et al (2018b) A high-throughput approach to identify specific neurotoxicants/developmental toxicants in human neuronal cell function assays. ALTEX 4:1. https://doi.org/10.14573/altex.1712182
doi: 10.14573/altex.1712182
Desprez B, Dent M, Keller D et al (2018) A strategy for systemic toxicity assessment based on non-animal approaches: the cosmetics Europe long range science strategy programme. Toxicol In Vitro 50:137–146. https://doi.org/10.1016/j.tiv.2018.02.017
doi: 10.1016/j.tiv.2018.02.017
pubmed: 29499337
Divakaruni AS, Rogers GW, Murphy AN (2014) Measuring mitochondrial function in permeabilized cells using the seahorse XF analyzer or a Clark-type oxygen electrode. Curr Protoc Toxicol 60:25. https://doi.org/10.1002/0471140856.tx2502s60
doi: 10.1002/0471140856.tx2502s60
pubmed: 24865647
Dott W, Mistry P, Wright J, Cain K, Herbert KE (2014) Modulation of mitochondrial bioenergetics in a skeletal muscle cell line model of mitochondrial toxicity. Redox Biol 2:224–233. https://doi.org/10.1016/j.redox.2013.12.028
doi: 10.1016/j.redox.2013.12.028
pubmed: 24494197
pmcid: 3909783
Dragovic S, Vermeulen NP, Gerets HH et al (2016) Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man. Arch Toxicol 90(12):2979–3003. https://doi.org/10.1007/s00204-016-1845-1
doi: 10.1007/s00204-016-1845-1
pubmed: 27659300
pmcid: 5104805
Dreinert A, Wolf A, Mentzel T, Meunier B, Fehr M (2018) The cytochrome bc1 complex inhibitor Ametoctradin has an unusual binding mode. Biochim Biophys Acta 1859(8):567–576. https://doi.org/10.1016/j.bbabio.2018.04.008
doi: 10.1016/j.bbabio.2018.04.008
Eakins J, Bauch C, Woodhouse H et al (2016) A combined in vitro approach to improve the prediction of mitochondrial toxicants. Toxicol In Vitro 34:161–170. https://doi.org/10.1016/j.tiv.2016.03.016
doi: 10.1016/j.tiv.2016.03.016
pubmed: 27083147
Efremova L, Schildknecht S, Adam M et al (2015) Prevention of the degeneration of human dopaminergic neurons in an astrocyte co-culture system allowing endogenous drug metabolism. Br J Pharmacol 172(16):4119–4132. https://doi.org/10.1111/bph.13193
doi: 10.1111/bph.13193
pubmed: 25989025
pmcid: 4543617
Forsby A, Bal-Price AK, Camins A et al (2009) Neuronal in vitro models for the estimation of acute systemic toxicity. Toxicol In Vitro 23(8):1564–1569. https://doi.org/10.1016/j.tiv.2009.07.017
doi: 10.1016/j.tiv.2009.07.017
pubmed: 19615435
FRAC FRAC (2011) FRAC code list: fungicides sorted by mode of action (including FRAC Code numbering)
Frank CL, Brown JP, Wallace K, Mundy WR, Shafer TJ (2017) From the cover: developmental neurotoxicants disrupt activity in cortical networks on microelectrode arrays: results of screening 86 compounds during neural network formation. Toxicol Sci 160(1):121–135. https://doi.org/10.1093/toxsci/kfx169
doi: 10.1093/toxsci/kfx169
pubmed: 28973552
Furlong IJ, Mediavilla CL, Ascaso R, Rivas AL, Collins MKL (1998) Induction of apoptosis by valinomycin: mitochondrial permeability transition causes intracellular acidification. Cell Death Differ 5:214. https://doi.org/10.1038/sj.cdd.4400335
doi: 10.1038/sj.cdd.4400335
pubmed: 10200467
Gantner F, Leist M, Jilg S, Germann PG, Freudenberg MA, Tiegs G (1995) Tumor necrosis factor-induced hepatic DNA fragmentation as an early marker of T cell-dependent liver injury in mice. Gastroenterology 109(1):166–176
doi: 10.1016/0016-5085(95)90282-1
Gerencser AA, Neilson A, Choi SW et al (2009) Quantitative microplate-based respirometry with correction for oxygen diffusion. Anal Chem 81(16):6868–6878. https://doi.org/10.1021/ac900881z
doi: 10.1021/ac900881z
pubmed: 19555051
pmcid: 2727168
Gonzalez PS, O’Prey J, Cardaci S et al (2018) Mannose impairs tumour growth and enhances chemotherapy. Nature 563(7733):719–723. https://doi.org/10.1038/s41586-018-0729-3
doi: 10.1038/s41586-018-0729-3
pubmed: 30464341
Gustafsson H, Runesson J, Lundqvist J, Lindegren H, Axelsson V, Forsby A (2010) Neurofunctional endpoints assessed in human neuroblastoma SH-SY5Y cells for estimation of acute systemic toxicity. Toxicol Appl Pharmacol 245(2):191–202. https://doi.org/10.1016/j.taap.2010.02.018
doi: 10.1016/j.taap.2010.02.018
pubmed: 20211194
Gutbier S, May P, Berthelot S et al (2018a) Major changes of cell function and toxicant sensitivity in cultured cells undergoing mild, quasi-natural genetic drift. Arch Toxicol. https://doi.org/10.1007/s00204-018-2326-5
doi: 10.1007/s00204-018-2326-5
pubmed: 30298209
pmcid: 6290691
Gutbier S, Spreng AS, Delp J et al (2018b) Prevention of neuronal apoptosis by astrocytes through thiol-mediated stress response modulation and accelerated recovery from proteotoxic stress. Cell Death Differ 25(12):2101–2117. https://doi.org/10.1038/s41418-018-0229-x
doi: 10.1038/s41418-018-0229-x
pubmed: 6261954
pmcid: 6261954
Harrill JA, Freudenrich TM, Robinette BL, Mundy WR (2011) Comparative sensitivity of human and rat neural cultures to chemical-induced inhibition of neurite outgrowth. Toxicol Appl Pharmacol 256(3):268–280. https://doi.org/10.1016/j.taap.2011.02.013
doi: 10.1016/j.taap.2011.02.013
pubmed: 21354195
Harrill JA, Freudenrich T, Wallace K, Ball K, Shafer TJ, Mundy WR (2018) Testing for developmental neurotoxicity using a battery of in vitro assays for key cellular events in neurodevelopment. Toxicol Appl Pharmacol 354:24–39. https://doi.org/10.1016/j.taap.2018.04.001
doi: 10.1016/j.taap.2018.04.001
pubmed: 29626487
He Y, Akumuo RC, Yang Y, Hewett SJ (2017) Mice deficient in L-12/15 lipoxygenase show increased vulnerability to 3-nitropropionic acid neurotoxicity. Neurosci Lett 643:65–69. https://doi.org/10.1016/j.neulet.2017.02.031
doi: 10.1016/j.neulet.2017.02.031
pubmed: 28229935
pmcid: 5383203
Hendriks HS, Meijer M, Muilwijk M, van den Berg M, Westerink RH (2014) A comparison of the in vitro cyto- and neurotoxicity of brominated and halogen-free flame retardants: prioritization in search for safe(r) alternatives. Arch Toxicol 88(4):857–869. https://doi.org/10.1007/s00204-013-1187-1
doi: 10.1007/s00204-013-1187-1
pubmed: 24395120
Hoelting L, Klima S, Karreman C et al (2016) Stem cell-derived immature human dorsal root ganglia neurons to identify peripheral neurotoxicants. Stem Cells Transl Med 5(4):476–487. https://doi.org/10.5966/sctm.2015-0108
doi: 10.5966/sctm.2015-0108
pubmed: 26933043
pmcid: 4798731
Huang Q, Cao H, Zhan L et al (2017) Mitochondrial fission forms a positive feedback loop with cytosolic calcium signaling pathway to promote autophagy in hepatocellular carcinoma cells. Cancer Lett 403:108–118. https://doi.org/10.1016/j.canlet.2017.05.034
doi: 10.1016/j.canlet.2017.05.034
pubmed: 28624623
Indo HP, Davidson M, Yen H-C et al (2007) Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage. Mitochondrion 7(1):106–118. https://doi.org/10.1016/j.mito.2006.11.026
doi: 10.1016/j.mito.2006.11.026
pubmed: 17307400
Jennings P, Schwarz M, Landesmann B et al (2014) SEURAT-1 liver gold reference compounds: a mechanism-based review. Arch Toxicol 88(12):2099–2133. https://doi.org/10.1007/s00204-014-1410-8
doi: 10.1007/s00204-014-1410-8
pubmed: 25395007
Jones W, Bianchi K (2015) Aerobic glycolysis: beyond proliferation. Front Immunol 6:227. https://doi.org/10.3389/fimmu.2015.00227
doi: 10.3389/fimmu.2015.00227
pubmed: 26029212
pmcid: 4432802
Kamalian L, Chadwick AE, Bayliss M et al (2015) The utility of HepG2 cells to identify direct mitochondrial dysfunction in the absence of cell death. Toxicol In Vitro 29(4):732–740. https://doi.org/10.1016/j.tiv.2015.02.011
doi: 10.1016/j.tiv.2015.02.011
pubmed: 25746382
Kinsner-Ovaskainen A, Prieto P, Stanzel S, Kopp-Schneider A (2013) Selection of test methods to be included in a testing strategy to predict acute oral toxicity: an approach based on statistical analysis of data collected in phase 1 of the ACuteTox project. Toxicol In Vitro 27(4):1377–1394. https://doi.org/10.1016/j.tiv.2012.11.010
doi: 10.1016/j.tiv.2012.11.010
pubmed: 23178337
Kohonen P, Parkkinen JA, Willighagen EL et al (2017) A transcriptomics data-driven gene space accurately predicts liver cytopathology and drug-induced liver injury. Nat Commun 8:15932. https://doi.org/10.1038/ncomms15932
doi: 10.1038/ncomms15932
pubmed: 28671182
pmcid: 5500850
Krug AK, Balmer NV, Matt F, Schonenberger F, Merhof D, Leist M (2013) Evaluation of a human neurite growth assay as specific screen for developmental neurotoxicants. Arch Toxicol 87(12):2215–2231. https://doi.org/10.1007/s00204-013-1072-y
doi: 10.1007/s00204-013-1072-y
pubmed: 23670202
Krug AK, Gutbier S, Zhao L et al (2014) Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP(+). Cell Death Dis 5:e1222. https://doi.org/10.1038/cddis.2014.166
doi: 10.1038/cddis.2014.166
pubmed: 24810058
pmcid: 4047858
Latta M, Kunstle G, Leist M, Wendel A (2000) Metabolic depletion of ATP by fructose inversely controls CD95- and tumor necrosis factor receptor 1-mediated hepatic apoptosis. J Exp Med 191(11):1975–1985
doi: 10.1084/jem.191.11.1975
Leist M, Nicotera P (1998) Calcium and neuronal death. Rev Physiol Biochem Pharmacol 132:79–125
doi: 10.1007/BFb0004986
Leist M, Gantner F, Bohlinger I, Tiegs G, Germann PG, Wendel A (1995) Tumor necrosis factor-induced hepatocyte apoptosis precedes liver failure in experimental murine shock models. Am J Pathol 146(5):1220–1234
pubmed: 7538266
pmcid: 1869293
Leist M, Fava E, Montecucco C, Nicotera P (1997a) Peroxynitrite and nitric oxide donors induce neuronal apoptosis by eliciting autocrine excitotoxicity. Eur J Neurosci 9(7):1488–1498
doi: 10.1111/j.1460-9568.1997.tb01503.x
Leist M, Single B, Castoldi AF, Kuhnle S, Nicotera P (1997b) Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 185(8):1481–1486
doi: 10.1084/jem.185.8.1481
Leist M, Volbracht C, Kuhnle S, Fava E, Ferrando-May E, Nicotera P (1997c) Caspase-mediated apoptosis in neuronal excitotoxicity triggered by nitric oxide. Mol Med (Cambridge, Mass) 3(11):750–764
doi: 10.1007/BF03401713
Leist M, Volbracht C, Fava E, Nicotera P (1998) 1-Methyl-4-phenylpyridinium induces autocrine excitotoxicity, protease activation, and neuronal apoptosis. Mol Pharmacol 54(5):789–801
doi: 10.1124/mol.54.5.789
Leist M, Single B, Naumann H et al (1999) Nitric oxide inhibits execution of apoptosis at two distinct ATP-dependent steps upstream and downstream of mitochondrial cytochrome c release. Biochem Biophys Res Commun 258(1):215–221. https://doi.org/10.1006/bbrc.1999.0491
doi: 10.1006/bbrc.1999.0491
pubmed: 10222263
Levy RJ (2017) Carbon monoxide and anesthesia-induced neurotoxicity. Neurotoxicol Teratol 60:50–58. https://doi.org/10.1016/j.ntt.2016.09.002
doi: 10.1016/j.ntt.2016.09.002
pubmed: 27616667
Li H, Zhu X-L, Yang W-C, Yang G-F (2014) Comparative kinetics of Qi site inhibitors of cytochrome bc1 complex: picomolar antimycin and micromolar cyazofamid. Chem Biol Drug Des 83(1):71–80. https://doi.org/10.1111/cbdd.12199
doi: 10.1111/cbdd.12199
pubmed: 23919901
Lümmen P (1998) Complex I inhibitors as insecticides and acaricides. Biochim Biophys Acta Bioenerg 1364(2):287–296. https://doi.org/10.1016/S0005-2728(98)00034-6
doi: 10.1016/S0005-2728(98)00034-6
Lunt SY, Vander Heiden MG (2011) Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol 27:441–464. https://doi.org/10.1146/annurev-cellbio-092910-154237
doi: 10.1146/annurev-cellbio-092910-154237
Marroquin LD, Hynes J, Dykens JA, Jamieson JD, Will Y (2007) Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants. Toxicol Sci 97(2):539–547. https://doi.org/10.1093/toxsci/kfm052
doi: 10.1093/toxsci/kfm052
pubmed: 17361016
Martin LA, Kennedy BE, Karten B (2016) Mitochondrial cholesterol: mechanisms of import and effects on mitochondrial function. J Bioenerg Biomembr 48(2):137–151. https://doi.org/10.1007/s10863-014-9592-6
doi: 10.1007/s10863-014-9592-6
pubmed: 25425472
Mitani M, Yamanishi T, Miyazaki Y (1975) Salinomycin: a new monovalent cation ionophore. Biochem Biophys Res Commun 66(4):1231–1236. https://doi.org/10.1016/0006-291x(75)90490-8
doi: 10.1016/0006-291x(75)90490-8
pubmed: 1191289
Mitani S, Araki S, Takii Y, Ohshima T, Matsuo N, Miyoshi H (2001) The biochemical mode of action of the novel selective fungicide cyazofamid: specific inhibition of mitochondrial complex III in Pythium spinosum. Pestic Biochem Physiol 71(2):107–115. https://doi.org/10.1006/pest.2001.2569
doi: 10.1006/pest.2001.2569
Nadanaciva S, Dykens JA, Bernal A, Capaldi RA, Will Y (2007) Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration. Toxicol Appl Pharmacol 223(3):277–287. https://doi.org/10.1016/j.taap.2007.06.003
doi: 10.1016/j.taap.2007.06.003
pubmed: 17658574
Nadanaciva S, Rana P, Beeson GC et al (2012) Assessment of drug-induced mitochondrial dysfunction via altered cellular respiration and acidification measured in a 96-well platform. J Bioenerg Biomembr 44(4):421–437. https://doi.org/10.1007/s10863-012-9446-z
doi: 10.1007/s10863-012-9446-z
pubmed: 22689143
Nauen R, Bretschneider T (2002) New modes of action of insecticides. Pestic Outlook 13(6):241–245. https://doi.org/10.1039/B211171N
doi: 10.1039/B211171N
Naujokat C, Fuchs D, Opelz G (2010) Salinomycin in cancer: a new mission for an old agent. Mol Med Rep 3(4):555–559. https://doi.org/10.3892/mmr_00000296
doi: 10.3892/mmr_00000296
pubmed: 21472278
Nicklas WJ, Vyas I, Heikkila RE (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci 36(26):2503–2508
doi: 10.1016/0024-3205(85)90146-8
Nicotera P, Leist M (1997) Energy supply and the shape of death in neurons and lymphoid cells. Cell Death Differ 4(6):435–442. https://doi.org/10.1038/sj.cdd.4400265
doi: 10.1038/sj.cdd.4400265
pubmed: 16465264
Nicotera P, Leist M, Manzo L (1999) Neuronal cell death: a demise with different shapes. Trends Pharmacol Sci 20(2):46–51
doi: 10.1016/S0165-6147(99)01304-8
Nordin-Andersson M, Walum E, Kjellstrand P, Forsby A (2003) Acrylamide-induced effects on general and neurospecific cellular functions during exposure and recovery. Cell Biol Toxicol 19(1):43–51
doi: 10.1023/A:1022017731328
O’Riordan TC, Fitzgerald K, Ponomarev GV et al (2007) Sensing intracellular oxygen using near-infrared phosphorescent probes and live-cell fluorescence imaging. Am J Physiol Regul Integrat Compar Physiol 292(4):R1613–R1620. https://doi.org/10.1152/ajpregu.00707.2006
doi: 10.1152/ajpregu.00707.2006
Pereira CV, Oliveira PJ, Will Y, Nadanaciva S (2012) Mitochondrial bioenergetics and drug-induced toxicity in a panel of mouse embryonic fibroblasts with mitochondrial DNA single nucleotide polymorphisms. Toxicol Appl Pharmacol 264(2):167–181. https://doi.org/10.1016/j.taap.2012.07.030
doi: 10.1016/j.taap.2012.07.030
pubmed: 22889881
Pereira SP, Deus CM, Serafim TL, Cunha-Oliveira T, Oliveira PJ (2018) Metabolic and phenotypic characterization of human skin fibroblasts after forcing oxidative capacity. Toxicol Sci 164(1):191–204. https://doi.org/10.1093/toxsci/kfy068
doi: 10.1093/toxsci/kfy068
pubmed: 29945227
Pessayre D, Fromenty B, Berson A et al (2012) Central role of mitochondria in drug-induced liver injury. Drug Metab Rev 44(1):34–87. https://doi.org/10.3109/03602532.2011.604086
doi: 10.3109/03602532.2011.604086
pubmed: 21892896
Pietzke M, Zasada C, Mudrich S, Kempa S (2014) Decoding the dynamics of cellular metabolism and the action of 3-bromopyruvate and 2-deoxyglucose using pulsed stable isotope-resolved metabolomics. Cancer Metab 2(9):9. https://doi.org/10.1186/2049-3002-2-9
doi: 10.1186/2049-3002-2-9
pubmed: 25035808
pmcid: 4101711
Poltl D, Schildknecht S, Karreman C, Leist M (2012) Uncoupling of ATP-depletion and cell death in human dopaminergic neurons. Neurotoxicology 33(4):769–779. https://doi.org/10.1016/j.neuro.2011.12.007
doi: 10.1016/j.neuro.2011.12.007
pubmed: 22206971
Porporato PE, Payen VL, Baselet B, Sonveaux P (2016) Metabolic changes associated with tumor metastasis, part 2: mitochondria, lipid and amino acid metabolism. Cell Mol Life Sci 73(7):1349–1363. https://doi.org/10.1007/s00018-015-2100-2
doi: 10.1007/s00018-015-2100-2
pubmed: 26646069
Rana P, Aleo MD, Gosink M, Will Y (2018) Evaluation of in vitro mitochondrial toxicity assays and physicochemical properties for prediction of organ toxicity using 228 pharmaceutical drugs. Chem Res Toxicol. https://doi.org/10.1021/acs.chemrestox.8b00246
doi: 10.1021/acs.chemrestox.8b00246
pubmed: 30525499
Reitzer LJ, Wice BM, Kennell D (1979) Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J Biol Chem 254(8):2669–2676
pubmed: 429309
Robinson BH, Petrova-Benedict R, Buncic JR, Wallace DC (1992) Nonviability of cells with oxidative defects in galactose medium: a screening test for affected patient fibroblasts. Biochem Med Metab Biol 48(2):122–126. https://doi.org/10.1016/0885-4505(92)90056-5
doi: 10.1016/0885-4505(92)90056-5
pubmed: 1329873
Salabei JK, Gibb AA, Hill BG (2014) Comprehensive measurement of respiratory activity in permeabilized cells using extracellular flux analysis. Nat Protoc 9(2):421–438. https://doi.org/10.1038/nprot.2014.018
doi: 10.1038/nprot.2014.018
pubmed: 24457333
pmcid: 4063296
Schildknecht S, Poltl D, Nagel DM et al (2009) Requirement of a dopaminergic neuronal phenotype for toxicity of low concentrations of 1-methyl-4-phenylpyridinium to human cells. Toxicol Appl Pharmacol 241(1):23–35. https://doi.org/10.1016/j.taap.2009.07.027
doi: 10.1016/j.taap.2009.07.027
pubmed: 19647008
Schildknecht S, Karreman C, Poltl D et al (2013) Generation of genetically-modified human differentiated cells for toxicological tests and the study of neurodegenerative diseases. Altex 30(4):427–444. https://doi.org/10.14573/altex.2013.4.427
doi: 10.14573/altex.2013.4.427
pubmed: 24173167
Schildknecht S, Di Monte DA, Pape R, Tieu K, Leist M (2017) Tipping points and endogenous determinants of nigrostriatal degeneration by MPTP. Trends Pharmacol Sci 38(6):541–555. https://doi.org/10.1016/j.tips.2017.03.010
doi: 10.1016/j.tips.2017.03.010
pubmed: 28442167
Schmidt BZ, Lehmann M, Gutbier S et al (2017) In vitro acute and developmental neurotoxicity screening: an overview of cellular platforms and high-throughput technical possibilities. Arch Toxicol 91(1):1–33. https://doi.org/10.1007/s00204-016-1805-9
doi: 10.1007/s00204-016-1805-9
pubmed: 27492622
Schmuck G, Kahl R (2009) The use of Fluoro-Jade in primary neuronal cell cultures. Arch Toxicol 83(4):397–403. https://doi.org/10.1007/s00204-008-0360-4
doi: 10.1007/s00204-008-0360-4
pubmed: 18815771
Scholz D, Poltl D, Genewsky A et al (2011) Rapid, complete and large-scale generation of post-mitotic neurons from the human LUHMES cell line. J Neurochem 119(5):957–971. https://doi.org/10.1111/j.1471-4159.2011.07255.x
doi: 10.1111/j.1471-4159.2011.07255.x
pubmed: 21434924
Schultz L, Zurich MG, Culot M et al (2015) Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in complementary CNS in vitro models. Toxicol In Vitro 30(1 Pt A):138–165. https://doi.org/10.1016/j.tiv.2015.05.016
doi: 10.1016/j.tiv.2015.05.016
pubmed: 26026931
Secker PF, Beneke S, Schlichenmaier N et al (2018) Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I: an off-target adverse effect. Cell Death Dis 9(2):226. https://doi.org/10.1038/s41419-018-0273-y
doi: 10.1038/s41419-018-0273-y
pubmed: 29445145
pmcid: 5833677
Senkowski W, Zhang X, Olofsson MH et al (2015) Three-dimensional cell culture-based screening identifies the anthelmintic drug nitazoxanide as a candidate for treatment of colorectal cancer. Mol Cancer Ther 14(6):1504–1516. https://doi.org/10.1158/1535-7163.Mct-14-0792
doi: 10.1158/1535-7163.Mct-14-0792
pubmed: 25911689
Sherer TB, Richardson JR, Testa CM et al (2007) Mechanism of toxicity of pesticides acting at complex I: relevance to environmental etiologies of Parkinson’s disease. J Neurochem 100(6):1469–1479. https://doi.org/10.1111/j.1471-4159.2006.04333.x
doi: 10.1111/j.1471-4159.2006.04333.x
pubmed: 17241123
Stiegler NV, Krug AK, Matt F, Leist M (2011) Assessment of chemical-induced impairment of human neurite outgrowth by multiparametric live cell imaging in high-density cultures. Toxicol Sci 121(1):73–87. https://doi.org/10.1093/toxsci/kfr034
doi: 10.1093/toxsci/kfr034
pubmed: 21342877
Swiss R, Niles A, Cali JJ, Nadanaciva S, Will Y (2013) Validation of a HTS-amenable assay to detect drug-induced mitochondrial toxicity in the absence and presence of cell death. Toxicol In Vitro 27(6):1789–1797. https://doi.org/10.1016/j.tiv.2013.05.007
doi: 10.1016/j.tiv.2013.05.007
pubmed: 23726864
Terrasso AP, Pinto C, Serra M et al (2015) Novel scalable 3D cell based model for in vitro neurotoxicity testing: combining human differentiated neurospheres with gene expression and functional endpoints. J Biotechnol 205:82–92. https://doi.org/10.1016/j.jbiotec.2014.12.011
doi: 10.1016/j.jbiotec.2014.12.011
pubmed: 25573798
Terron A, Bal-Price A, Paini A et al (2018) An adverse outcome pathway for parkinsonian motor deficits associated with mitochondrial complex I inhibition. Arch Toxicol 92(1):41–82. https://doi.org/10.1007/s00204-017-2133-4
doi: 10.1007/s00204-017-2133-4
Tilmant K, Gerets H, De Ron P, Hanon E, Bento-Pereira C, Atienzar FA (2018) In vitro screening of cell bioenergetics to assess mitochondrial dysfunction in drug development. Toxicol In Vitro 52:374–383. https://doi.org/10.1016/j.tiv.2018.07.012
doi: 10.1016/j.tiv.2018.07.012
pubmed: 30030051
Tirmenstein MA, Hu CX, Gales TL et al (2002) Effects of troglitazone on HepG2 viability and mitochondrial function. Toxicol Sci 69(1):131–138
doi: 10.1093/toxsci/69.1.131
Tong ZB, Hogberg H, Kuo D et al (2017) Characterization of three human cell line models for high-throughput neuronal cytotoxicity screening. J Appl Toxicol 37(2):167–180. https://doi.org/10.1002/jat.3334
doi: 10.1002/jat.3334
pubmed: 27143523
Tong ZB, Huang R, Wang Y et al (2018) The toxmatrix: chemo-genomic profiling identifies interactions that reveal mechanisms of toxicity. Chem Res Toxicol 31(2):127–136. https://doi.org/10.1021/acs.chemrestox.7b00290
doi: 10.1021/acs.chemrestox.7b00290
pubmed: 29156121
van Thriel C, Levin E, Lein P, Costa LG, Westerink RH (2017) Neural mechanisms of functional impairment across the lifespan: the 15th biennial meeting of the international neurotoxicology association and 39th annual meeting of the neurobehavioral teratology society. Neurotoxicology 59:131–132. https://doi.org/10.1016/j.neuro.2017.03.003
doi: 10.1016/j.neuro.2017.03.003
pubmed: 28347437
Volbracht C, Leist M, Nicotera P (1999) ATP controls neuronal apoptosis triggered by microtubule breakdown or potassium deprivation. Mol Med (Cambridge, Mass) 5(7):477–489
doi: 10.1007/BF03403541
Wajner M, Amaral AU (2015) Mitochondrial dysfunction in fatty acid oxidation disorders: insights from human and animal studies. Biosci Rep 36(1):e00281. https://doi.org/10.1042/bsr20150240
doi: 10.1042/bsr20150240
pubmed: 26589966
Westwood FR, Bigley A, Randall K, Marsden AM, Scott RC (2005) Statin-induced muscle necrosis in the rat: distribution, development, and fibre selectivity. Toxicol Pathol 33(2):246–257. https://doi.org/10.1080/01926230590908213
doi: 10.1080/01926230590908213
pubmed: 15902968
Will Y, Dykens J (2014) Mitochondrial toxicity assessment in industry—a decade of technology development and insight. Expert Opin Drug Metab Toxicol 10(8):1061–1067. https://doi.org/10.1517/17425255.2014.939628
doi: 10.1517/17425255.2014.939628
pubmed: 25023361
Wilson MS, Graham JR, Ball AJ (2014) Multiparametric high content analysis for assessment of neurotoxicity in differentiated neuronal cell lines and human embryonic stem cell-derived neurons. Neurotoxicology 42:33–48. https://doi.org/10.1016/j.neuro.2014.03.013
doi: 10.1016/j.neuro.2014.03.013
pubmed: 24705302
Witt B, Meyer S, Ebert F, Francesconi KA, Schwerdtle T (2017) Toxicity of two classes of arsenolipids and their water-soluble metabolites in human differentiated neurons. Arch Toxicol 91(9):3121–3134. https://doi.org/10.1007/s00204-017-1933-x
doi: 10.1007/s00204-017-1933-x
pubmed: 28180949
Wolters JEJ, van Breda SGJ, Grossmann J, Fortes C, Caiment F, Kleinjans JCS (2018) Integrated ‘omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett 289:1–13. https://doi.org/10.1016/j.toxlet.2018.02.026
doi: 10.1016/j.toxlet.2018.02.026
pubmed: 29501571
Xia M, Huang R, Shi Q et al (2018) Comprehensive analyses and prioritization of Tox21 10 K chemicals affecting mitochondrial function by in-depth mechanistic studies. Environ Health Perspect 126(7):077010. https://doi.org/10.1289/ehp2589
doi: 10.1289/ehp2589
pubmed: 30059008
pmcid: 6112376
Yu LP, Xiang S, Lasso G, Gil D, Valle M, Tong L (2009) A symmetrical tetramer for S. aureus pyruvate carboxylase in complex with coenzyme A. Structure (London, England : 1993) 17(6):823–832. https://doi.org/10.1016/j.str.2009.04.008
doi: 10.1016/j.str.2009.04.008
Zhang Y, Avalos JL (2017) Traditional and novel tools to probe the mitochondrial metabolism in health and disease. Wiley Interdiscip Rev Syst Biol Med 9:2. https://doi.org/10.1002/wsbm.1373
doi: 10.1002/wsbm.1373
Zhang CQ, Liu YH, Ma XY, Feng Z, Ma ZH (2009) Characterization of sensitivity of Rhizoctonia solani, causing rice sheath blight, to mepronil and boscalid. Crop Protection 28(5):381–386. https://doi.org/10.1016/j.cropro.2008.12.004
doi: 10.1016/j.cropro.2008.12.004
Zimmer B, Schildknecht S, Kuegler PB, Tanavde V, Kadereit S, Leist M (2011) Sensitivity of dopaminergic neuron differentiation from stem cells to chronic low-dose methylmercury exposure. Toxicol Sci 121(2):357–367. https://doi.org/10.1093/toxsci/kfr054
doi: 10.1093/toxsci/kfr054
pubmed: 21385734