biostudies-literatureValentin Gese GVetenskapsrådetVetenskapsrådet (VR)Knut och Alice Wallenbergs StiftelseKnut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)6573-6590https://www.ebi.ac.uk/biostudies/studies/S-EPMC11649783biostudies-literatureUnknown43(24)Maturation of human mitochondrial tRNA is essential for cellular energy production, yet the underlying mechanisms remain only partially understood. Here, we present several cryo-EM structures of the mitochondrial RNase Z complex (ELAC2/SDR5C1/TRMT10C) bound to different maturation states of mitochondrial tRNA^His, showing the molecular basis for tRNA-substrate selection and catalysis. Our structural insights provide a molecular rationale for the 5'-to-3' tRNA processing order in mitochondria, the 3'-CCA antideterminant effect, and the basis for sequence-independent recognition of mitochondrial tRNA substrates. Furthermore, our study links mutations in ELAC2 to clinically relevant mitochondrial diseases, offering a deeper understanding of the molecular defects contributing to thesThe EMBO journalStructural basis of 3'-tRNA maturation by the human mitochondrial RNase Z complex.PMC116497832017.00802022-023262018.00802018-03808Valentin Gese GHallberg BMfalseStructural basis of 3'-tRNA maturation by the human mitochondrial RNase Z complex.Maturation of human mitochondrial tRNA is essential for cellular energy production, yet the underlying mechanisms remain only partially understood. Here, we present several cryo-EM structures of the mitochondrial RNase Z complex (ELAC2/SDR5C1/TRMT10C) bound to different maturation states of mitochondrial tRNA^His, showing the molecular basis for tRNA-substrate selection and catalysis. Our structural insights provide a molecular rationale for the 5'-to-3' tRNA processing order in mitochondria, the 3'-CCA antideterminant effect, and the basis for sequence-independent recognition of mitochondrial tRNA substrates. Furthermore, our study links mutations in ELAC2 to clinically relevant mitochondrial diseases, offering a deeper understanding of the molecular defects contributing to thes2024-01-01T00:00:00Z2024 Dec2026-06-02T18:04:48.488Z2025-04-04T21:45:55.96ZS-EPMC116497833951628110.1038/s44318-024-00297-w