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Lithium increases mitochondrial respiration in iPSC-derived neural precursor cells from lithium responders
Lithium (Li), valproate (VPA) and lamotrigine (LTG) are commonly used to treat bipolar disorder (BD). While their clinical efficacy is well established, the mechanisms of action at the molecular level are still incompletely understood. Here we investigated the molecular effects of Li, LTG and VPA tr...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760072/ https://www.ncbi.nlm.nih.gov/pubmed/34075196 http://dx.doi.org/10.1038/s41380-021-01164-4 |
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author | Osete, Jordi Requena Akkouh, Ibrahim A. de Assis, Denis Reis Szabo, Attila Frei, Evgeniia Hughes, Timothy Smeland, Olav B. Steen, Nils Eiel Andreassen, Ole A. Djurovic, Srdjan |
author_facet | Osete, Jordi Requena Akkouh, Ibrahim A. de Assis, Denis Reis Szabo, Attila Frei, Evgeniia Hughes, Timothy Smeland, Olav B. Steen, Nils Eiel Andreassen, Ole A. Djurovic, Srdjan |
author_sort | Osete, Jordi Requena |
collection | PubMed |
description | Lithium (Li), valproate (VPA) and lamotrigine (LTG) are commonly used to treat bipolar disorder (BD). While their clinical efficacy is well established, the mechanisms of action at the molecular level are still incompletely understood. Here we investigated the molecular effects of Li, LTG and VPA treatment in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) generated from 3 healthy controls (CTRL), 3 affective disorder Li responsive patients (Li-R) and 3 Li non-treated patients (Li-N) after 6 h and 1 week of exposure. Differential expression (DE) analysis after 6 h of treatment revealed a transcriptional signature that was associated with all three drugs and most significantly enriched for ribosome and oxidative phosphorylation (OXPHOS) pathways. In addition to the shared DE genes, we found that Li exposure was associated with 554 genes uniquely regulated in Li-R NPCs and enriched for spliceosome, OXPHOS and thermogenesis pathways. In-depth analysis of the treatment-associated transcripts uncovered a significant decrease in intron retention rate, suggesting that the beneficial influence of these drugs might partly be related to splicing. We examined the mitochondrial respiratory function of the NPCs by exploring the drugs’ effects on oxygen consumption rate (OCR) and glycolytic rate (ECAR). Li improved OCR levels only in Li-R NPCs by enhancing maximal respiration and reserve capacity, while VPA enhanced maximal respiration and reserve capacity in Li-N NPCs. Overall, our findings further support the involvement of mitochondrial functions in the molecular mechanisms of mood stabilizers and suggest novel mechanisms related to the spliceosome, which warrant further investigation. |
format | Online Article Text |
id | pubmed-8760072 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-87600722022-01-26 Lithium increases mitochondrial respiration in iPSC-derived neural precursor cells from lithium responders Osete, Jordi Requena Akkouh, Ibrahim A. de Assis, Denis Reis Szabo, Attila Frei, Evgeniia Hughes, Timothy Smeland, Olav B. Steen, Nils Eiel Andreassen, Ole A. Djurovic, Srdjan Mol Psychiatry Article Lithium (Li), valproate (VPA) and lamotrigine (LTG) are commonly used to treat bipolar disorder (BD). While their clinical efficacy is well established, the mechanisms of action at the molecular level are still incompletely understood. Here we investigated the molecular effects of Li, LTG and VPA treatment in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) generated from 3 healthy controls (CTRL), 3 affective disorder Li responsive patients (Li-R) and 3 Li non-treated patients (Li-N) after 6 h and 1 week of exposure. Differential expression (DE) analysis after 6 h of treatment revealed a transcriptional signature that was associated with all three drugs and most significantly enriched for ribosome and oxidative phosphorylation (OXPHOS) pathways. In addition to the shared DE genes, we found that Li exposure was associated with 554 genes uniquely regulated in Li-R NPCs and enriched for spliceosome, OXPHOS and thermogenesis pathways. In-depth analysis of the treatment-associated transcripts uncovered a significant decrease in intron retention rate, suggesting that the beneficial influence of these drugs might partly be related to splicing. We examined the mitochondrial respiratory function of the NPCs by exploring the drugs’ effects on oxygen consumption rate (OCR) and glycolytic rate (ECAR). Li improved OCR levels only in Li-R NPCs by enhancing maximal respiration and reserve capacity, while VPA enhanced maximal respiration and reserve capacity in Li-N NPCs. Overall, our findings further support the involvement of mitochondrial functions in the molecular mechanisms of mood stabilizers and suggest novel mechanisms related to the spliceosome, which warrant further investigation. Nature Publishing Group UK 2021-06-01 2021 /pmc/articles/PMC8760072/ /pubmed/34075196 http://dx.doi.org/10.1038/s41380-021-01164-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Osete, Jordi Requena Akkouh, Ibrahim A. de Assis, Denis Reis Szabo, Attila Frei, Evgeniia Hughes, Timothy Smeland, Olav B. Steen, Nils Eiel Andreassen, Ole A. Djurovic, Srdjan Lithium increases mitochondrial respiration in iPSC-derived neural precursor cells from lithium responders |
title | Lithium increases mitochondrial respiration in iPSC-derived neural precursor cells from lithium responders |
title_full | Lithium increases mitochondrial respiration in iPSC-derived neural precursor cells from lithium responders |
title_fullStr | Lithium increases mitochondrial respiration in iPSC-derived neural precursor cells from lithium responders |
title_full_unstemmed | Lithium increases mitochondrial respiration in iPSC-derived neural precursor cells from lithium responders |
title_short | Lithium increases mitochondrial respiration in iPSC-derived neural precursor cells from lithium responders |
title_sort | lithium increases mitochondrial respiration in ipsc-derived neural precursor cells from lithium responders |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760072/ https://www.ncbi.nlm.nih.gov/pubmed/34075196 http://dx.doi.org/10.1038/s41380-021-01164-4 |
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