| Autor: |
Di Michele Michela, Attina Aurore, Laguesse Sophie, De Blasio Carlo, Wendling Olivia, Frenois Francois-Xavier, Encislai Betty, Fuentes Maryse, Jahanault-Tagliani Céline, Rousseau Mélanie, Roux Pierre-François, Guégan Justine, Buscail Yoan, Dupré Pierrick, Michaud Henri-Alexandre, Rodier Geneviève, Bellvert Floriant, Kulyk Barbier Hannah, Ferraro Peyret Carole, Mathieu Hugo, Chaveroux Cédric, Pirot Nelly, Rubio Lucie, Torro Adeline, Compan Vincent, Sorg Tania, Ango Fabrice, David Alexandre, Lebigot Elise, Legati Andrea, Hirtz Christophe, Ghezzi Daniele, Nguyen Laurent, Sardet Claude, Lacroix Matthieu, Le Cam Laurent |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.12.19.521032 |
| Popis: |
SUMMARYThe Leigh syndrome is a severe inborn neurodegenerative encephalopathy commonly associated with pyruvate metabolism defects. The transcription factor E4F1, a key regulator of the pyruvate dehydrogenase (PDH) complex (PDC), was previously found to be mutated in Leigh syndrome patients, but the molecular mechanisms leading to cell death in E4F1-deficient neurons remain unknown. Here, we show that E4F1 directly regulatesDlatandElp3, two genes encoding key subunits of the PDC and of the Elongator complex, to coordinate AcetylCoenzyme A production and its utilization to acetylate tRNAs. Genetic inactivation ofE4f1in neurons during mouse embryonic development impaired tRNAs editing and induced an ATF4-mediated integrated stress response (ISR), leading to neuronal cell death and microcephaly. Furthermore, our analysis of PDH-deficient cells unraveled a crosstalk linking the PDC to ELP3 expression that is perturbed in Leigh syndrome patients. Altogether, our data support a model where pyruvate metabolism regulates the epitranscriptome to ensure protein translation fidelity. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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