E4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure translation fidelity during brain development
Abstract Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that plays an es...
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2025-01-01
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| author | Michela Di Michele Aurore Attina Pierre-François Roux Imène Tabet Sophie Laguesse Javier Florido Morane Houdeville Armelle Choquet Betty Encislai Giuseppe Arena Carlo De Blasio Olivia Wendling François-Xavier Frenois Laura Papon Lucille Stuani Maryse Fuentes Céline Jahannault Talignani Mélanie Rousseau Justine Guégan Yoan Buscail Pierrick Dupré Henri-Alexandre Michaud Geneviève Rodier Floriant Bellvert Hanna Kulyk Carole Ferraro Peyret Hugo Mathieu Pierre Close Francesca Rapino Cédric Chaveroux Nelly Pirot Lucie Rubio Adeline Torro Tania Sorg Fabrice Ango Christophe Hirtz Vincent Compan Elise Lebigot Andrea Legati Daniele Ghezzi Laurent Nguyen Alexandre David Claude Sardet Matthieu Lacroix Laurent Le Cam |
| author_facet | Michela Di Michele Aurore Attina Pierre-François Roux Imène Tabet Sophie Laguesse Javier Florido Morane Houdeville Armelle Choquet Betty Encislai Giuseppe Arena Carlo De Blasio Olivia Wendling François-Xavier Frenois Laura Papon Lucille Stuani Maryse Fuentes Céline Jahannault Talignani Mélanie Rousseau Justine Guégan Yoan Buscail Pierrick Dupré Henri-Alexandre Michaud Geneviève Rodier Floriant Bellvert Hanna Kulyk Carole Ferraro Peyret Hugo Mathieu Pierre Close Francesca Rapino Cédric Chaveroux Nelly Pirot Lucie Rubio Adeline Torro Tania Sorg Fabrice Ango Christophe Hirtz Vincent Compan Elise Lebigot Andrea Legati Daniele Ghezzi Laurent Nguyen Alexandre David Claude Sardet Matthieu Lacroix Laurent Le Cam |
| author_sort | Michela Di Michele |
| collection | DOAJ |
| description | Abstract Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that plays an essential role during brain development. Using genetically engineered mouse model and primary neuronal cells, we identify the transcription factor E4F1 as a key coordinator of AcetylCoenzyme A (AcCoA) production by the pyruvate dehydrogenase complex (PDC) and its utilization as an essential co-factor by the Elongator complex to acetylate tRNAs at the wobble position uridine 34 (U34). E4F1-mediated direct transcriptional regulation of Dlat and Elp3, two genes encoding key subunits of the PDC and of the Elongator complex, respectively, ensures proper translation fidelity and cell survival in the central nervous system (CNS) during mouse embryonic development. Furthermore, analysis of PDH-deficient cells highlight a crosstalk linking the PDC to ELP3 expression that is perturbed in LS patients. |
| format | Article |
| id | doaj-art-8c3c3af22cdd4eb2b62644f004b121a2 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-8c3c3af22cdd4eb2b62644f004b121a22025-01-05T12:37:30ZengNature PortfolioNature Communications2041-17232025-01-0116111710.1038/s41467-024-55444-yE4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure translation fidelity during brain developmentMichela Di Michele0Aurore Attina1Pierre-François Roux2Imène Tabet3Sophie Laguesse4Javier Florido5Morane Houdeville6Armelle Choquet7Betty Encislai8Giuseppe Arena9Carlo De Blasio10Olivia Wendling11François-Xavier Frenois12Laura Papon13Lucille Stuani14Maryse Fuentes15Céline Jahannault Talignani16Mélanie Rousseau17Justine Guégan18Yoan Buscail19Pierrick Dupré20Henri-Alexandre Michaud21Geneviève Rodier22Floriant Bellvert23Hanna Kulyk24Carole Ferraro Peyret25Hugo Mathieu26Pierre Close27Francesca Rapino28Cédric Chaveroux29Nelly Pirot30Lucie Rubio31Adeline Torro32Tania Sorg33Fabrice Ango34Christophe Hirtz35Vincent Compan36Elise Lebigot37Andrea Legati38Daniele Ghezzi39Laurent Nguyen40Alexandre David41Claude Sardet42Matthieu Lacroix43Laurent Le Cam44Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)IRMB-PPC, Univ. Montpellier, INSERM, CHU Montpellier, CNRSInstitut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Liège, CHU Sart TilmanInstitut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Luxembourg Centre for Systems Biomedicine (LCSB), University of LuxembourgInstitut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Université de Strasbourg, CNRS, INSERM, CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS)Department of Pathology, CHU, Imag’IN Platform, IUCT-OncopoleInstitut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Data Analysis Core Platform, Institut du Cerveau – Paris Brain Institute - ICM, Sorbonne Université, INSERM, CNRS, APHP, Hôpital de la Pitié-SalpêtrièreInstitut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)MetaToul-MetaboHUB, National Infrastructure of Metabolomics and FluxomicsMetaToul-MetaboHUB, National Infrastructure of Metabolomics and FluxomicsUniv. Lyon, Claude Bernard University, LBTI UMR CNRS 5305, Faculty of PharmacyInstitut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Laboratory of Cancer Signaling, GIGA-Institute, University of LiègeLaboratory of Cancer Signaling, GIGA-Institute, University of LiègeUniv. Lyon, Claude Bernard University, LBTI UMR CNRS 5305, Faculty of PharmacyInstitut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Université de Strasbourg, CNRS, INSERM, CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS)Institut des Neurosciences de Montpellier, Université de Montpellier, INSERM, CNRSIRMB-PPC, Univ. Montpellier, INSERM, CHU Montpellier, CNRSInstitut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERMBiochemistry Department, Bicêtre Hospital, APHP Paris SaclayUnit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo BestaUnit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo BestaLaboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Liège, CHU Sart TilmanInstitut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Univ. Montpellier, Institut régional du Cancer de Montpellier (ICM)Abstract Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that plays an essential role during brain development. Using genetically engineered mouse model and primary neuronal cells, we identify the transcription factor E4F1 as a key coordinator of AcetylCoenzyme A (AcCoA) production by the pyruvate dehydrogenase complex (PDC) and its utilization as an essential co-factor by the Elongator complex to acetylate tRNAs at the wobble position uridine 34 (U34). E4F1-mediated direct transcriptional regulation of Dlat and Elp3, two genes encoding key subunits of the PDC and of the Elongator complex, respectively, ensures proper translation fidelity and cell survival in the central nervous system (CNS) during mouse embryonic development. Furthermore, analysis of PDH-deficient cells highlight a crosstalk linking the PDC to ELP3 expression that is perturbed in LS patients.https://doi.org/10.1038/s41467-024-55444-y |
| spellingShingle | Michela Di Michele Aurore Attina Pierre-François Roux Imène Tabet Sophie Laguesse Javier Florido Morane Houdeville Armelle Choquet Betty Encislai Giuseppe Arena Carlo De Blasio Olivia Wendling François-Xavier Frenois Laura Papon Lucille Stuani Maryse Fuentes Céline Jahannault Talignani Mélanie Rousseau Justine Guégan Yoan Buscail Pierrick Dupré Henri-Alexandre Michaud Geneviève Rodier Floriant Bellvert Hanna Kulyk Carole Ferraro Peyret Hugo Mathieu Pierre Close Francesca Rapino Cédric Chaveroux Nelly Pirot Lucie Rubio Adeline Torro Tania Sorg Fabrice Ango Christophe Hirtz Vincent Compan Elise Lebigot Andrea Legati Daniele Ghezzi Laurent Nguyen Alexandre David Claude Sardet Matthieu Lacroix Laurent Le Cam E4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure translation fidelity during brain development Nature Communications |
| title | E4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure translation fidelity during brain development |
| title_full | E4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure translation fidelity during brain development |
| title_fullStr | E4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure translation fidelity during brain development |
| title_full_unstemmed | E4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure translation fidelity during brain development |
| title_short | E4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure translation fidelity during brain development |
| title_sort | e4f1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure translation fidelity during brain development |
| url | https://doi.org/10.1038/s41467-024-55444-y |
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