E4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure translation fidelity during brain development

Michela Michele (), Aurore Attina, Pierre-François Roux, Imène Tabet, Sophie Laguesse, Javier Florido, Morane Houdeville, Armelle Choquet, Betty Encislai, Giuseppe Arena, Carlo 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 () and Laurent Cam ()
Additional contact information
Michela Michele: Institut régional du Cancer de Montpellier (ICM)
Aurore Attina: CNRS
Pierre-François Roux: Institut régional du Cancer de Montpellier (ICM)
Imène Tabet: Institut régional du Cancer de Montpellier (ICM)
Sophie Laguesse: CHU Sart Tilman
Javier Florido: Institut régional du Cancer de Montpellier (ICM)
Morane Houdeville: Institut régional du Cancer de Montpellier (ICM)
Armelle Choquet: Institut régional du Cancer de Montpellier (ICM)
Betty Encislai: Institut régional du Cancer de Montpellier (ICM)
Giuseppe Arena: University of Luxembourg
Carlo Blasio: Institut régional du Cancer de Montpellier (ICM)
Olivia Wendling: Institut Clinique de la Souris (ICS)
François-Xavier Frenois: IUCT-Oncopole
Laura Papon: Institut régional du Cancer de Montpellier (ICM)
Lucille Stuani: Institut régional du Cancer de Montpellier (ICM)
Maryse Fuentes: Institut régional du Cancer de Montpellier (ICM)
Céline Jahannault Talignani: Institut régional du Cancer de Montpellier (ICM)
Mélanie Rousseau: Institut régional du Cancer de Montpellier (ICM)
Justine Guégan: Hôpital de la Pitié-Salpêtrière
Yoan Buscail: Institut régional du Cancer de Montpellier (ICM)
Pierrick Dupré: Institut régional du Cancer de Montpellier (ICM)
Henri-Alexandre Michaud: Institut régional du Cancer de Montpellier (ICM)
Geneviève Rodier: Institut régional du Cancer de Montpellier (ICM)
Floriant Bellvert: National Infrastructure of Metabolomics and Fluxomics
Hanna Kulyk: National Infrastructure of Metabolomics and Fluxomics
Carole Ferraro Peyret: Faculty of Pharmacy
Hugo Mathieu: Institut régional du Cancer de Montpellier (ICM)
Pierre Close: University of Liège
Francesca Rapino: University of Liège
Cédric Chaveroux: Faculty of Pharmacy
Nelly Pirot: Institut régional du Cancer de Montpellier (ICM)
Lucie Rubio: Institut régional du Cancer de Montpellier (ICM)
Adeline Torro: Institut régional du Cancer de Montpellier (ICM)
Tania Sorg: Institut Clinique de la Souris (ICS)
Fabrice Ango: CNRS
Christophe Hirtz: CNRS
Vincent Compan: INSERM
Elise Lebigot: APHP Paris Saclay
Andrea Legati: Fondazione IRCCS Istituto Neurologico Carlo Besta
Daniele Ghezzi: Fondazione IRCCS Istituto Neurologico Carlo Besta
Laurent Nguyen: CHU Sart Tilman
Alexandre David: Institut régional du Cancer de Montpellier (ICM)
Claude Sardet: Institut régional du Cancer de Montpellier (ICM)
Matthieu Lacroix: Institut régional du Cancer de Montpellier (ICM)
Laurent Cam: Institut régional du Cancer de Montpellier (ICM)

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-55444-y

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