Description

Mitochondria are central to ATP production, especially in energy-demanding heart and brain tissues. Defects in mitochondrial translation, often caused by missing post-transcriptional modifications of mitochondrial tRNAs, are a major cause of severe diseases. Among these, the C5-taurinomethylation of uridine 34 (τm5U34), catalyzed by the GTPBP3-MTO1complex, is essential for translation fidelity and respiratory chain function. Clinical mutations in genes encoding this complex cause the mitochondrial syndrome COXPD23 associated with cardiomyopathies or encephalopathies. The enzymatic reaction requires a complex set of cofactors and substrates including GTP, FAD, NADH, taurine and a folate derivative. Currently, the enzymatic mechanism, structural organization, and cellular consequences of the corresponding pathological mutations in GTPBP3 and MTO1 remain poorly understood.

In this proposed Ph.D. project, the candidate will pursue two main objectives: (1) reconstitute the tRNA modification pathway in vitro to define catalytic steps and assess the impact of clinical variants through biochemical techniques; (2) resolve the structural basis of enzyme cooperation using biophysical tools, X-ray crystallography, and cryo-EM. This project will deliver the first complete biochemical and structural mechanism of τm5U34 synthesis, explaining how its disruption is linked to pathologies, and open new avenues for therapeutic strategies against rare mitochondrial disorders.