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Stage-specific metabolic features of differentiating neurons : Implications for toxicant sensitivity

Stage-specific metabolic features of differentiating neurons : Implications for toxicant sensitivity

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DELP, Johannes, Simon GUTBIER, Martin CERFF, Thomas HARTUNG, Hanna BORLINGHAUS, Falk SCHREIBER, Tanja WALDMANN, Stefan KEMPA, Katharina NÖH, Marcel LEIST, 2018. Stage-specific metabolic features of differentiating neurons : Implications for toxicant sensitivity. In: Toxicology and Applied Pharmacology. 354, pp. 64-80. ISSN 0041-008X. eISSN 1096-0333. Available under: doi: 10.1016/j.taap.2017.12.013

@article{Delp2018-09Stage-41182, title={Stage-specific metabolic features of differentiating neurons : Implications for toxicant sensitivity}, year={2018}, doi={10.1016/j.taap.2017.12.013}, volume={354}, issn={0041-008X}, journal={Toxicology and Applied Pharmacology}, pages={64--80}, author={Delp, Johannes and Gutbier, Simon and Cerff, Martin and Hartung, Thomas and Borlinghaus, Hanna and Schreiber, Falk and Waldmann, Tanja and Kempa, Stefan and Nöh, Katharina and Leist, Marcel}, note={Corrigendum: https://doi.org/10.1016/j.taap.2019.04.010} }

Borlinghaus, Hanna Cerff, Martin Leist, Marcel Nöh, Katharina Hartung, Thomas Schreiber, Falk eng Gutbier, Simon Stage-specific metabolic features of differentiating neurons : Implications for toxicant sensitivity Delp, Johannes Kempa, Stefan 2018-01-31T14:03:58Z Schreiber, Falk terms-of-use Kempa, Stefan Waldmann, Tanja 2018-09 Leist, Marcel 2018-01-31T14:03:58Z Hartung, Thomas Nöh, Katharina Cerff, Martin Gutbier, Simon Waldmann, Tanja Delp, Johannes Borlinghaus, Hanna Developmental neurotoxicity (DNT) may be induced when chemicals disturb a key neurodevelopmental process, and many tests focus on this type of toxicity. Alternatively, DNT may occur when chemicals are cytotoxic only during a specific neurodevelopmental stage. The toxicant sensitivity is affected by the expression of toxicant targets and by resilience factors. Although cellular metabolism plays an important role, little is known how it changes during human neurogenesis, and how potential alterations affect toxicant sensitivity of mature vs. immature neurons. We used immature (d0) and mature (d6) LUHMES cells (dopaminergic human neurons) to provide initial answers to these questions. Transcriptome profiling and characterization of energy metabolism suggested a switch from predominantly glycolytic energy generation to a more pronounced contribution of the tricarboxylic acid cycle (TCA) during neuronal maturation. Therefore, we used pulsed stable isotope-resolved metabolomics (pSIRM) to determine intracellular metabolite pool sizes (concentrations), and isotopically non-stationary <sup>13</sup>C-metabolic flux analysis (INST <sup>13</sup>C-MFA) to calculate metabolic fluxes. We found that d0 cells mainly use glutamine to fuel the TCA. Furthermore, they rely on extracellular pyruvate to allow continuous growth. This metabolic situation does not allow for mitochondrial or glycolytic spare capacity, i.e. the ability to adapt energy generation to altered needs. Accordingly, neuronal precursor cells displayed a higher sensitivity to several mitochondrial toxicants than mature neurons differentiated from them. In summary, this study shows that precursor cells lose their glutamine dependency during differentiation while they gain flexibility of energy generation and thereby increase their resistance to low concentrations of mitochondrial toxicants.

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