The 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 regulates Dlat and Elp3, 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 of E4f1 in 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.