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

Date publication

janvier 2025

Journal

Nature communications

Auteurs

Membres identifiés du Cancéropôle Est :
Dr SORG Tania

Tous les auteurs :
Di Michele M, Attina A, Roux PF, Tabet I, Laguesse S, Florido J, Houdeville M, Choquet A, Encislai B, Arena G, De Blasio C, Wendling O, Frenois FX, Papon L, Stuani L, Fuentes M, Jahannault Talignani C, Rousseau M, Guégan J, Buscail Y, Dupré P, Michaud HA, Rodier G, Bellvert F, Kulyk H, Ferraro Peyret C, Mathieu H, Close P, Rapino F, Chaveroux C, Pirot N, Rubio L, Torro A, Sorg T, Ango F, Hirtz C, Compan V, Lebigot E, Legati A, Ghezzi D, Nguyen L, David A, Sardet C, Lacroix M, Le Cam L

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/39747033

Résumé

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 (U). 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.

Mots clés

Animals, Brain, metabolism, Mice, Humans, Pyruvic Acid, metabolism, Pyruvate Dehydrogenase Complex, metabolism, Leigh Disease, metabolism, Neurons, metabolism, RNA, Transfer, metabolism, Protein Biosynthesis, Gene Expression Regulation, Developmental, Dihydrolipoyllysine-Residue Acetyltransferase, metabolism, Basic-Leucine Zipper Transcription Factors, metabolism, Mice, Knockout, Mice, Inbred C57BL, Uridine, metabolism, Female, Nerve Tissue Proteins, Histone Acetyltransferases

Référence

Nat Commun. 2025 01 2;16(1):67