2025/10/21 by Nils Bertram, Toshiaki Izawa, Felix Thoma +8 · 1 voice
Biochemistry, Genetics and Molecular Biology · Neuroscience · #Endoplasmic Reticulum Stress and Disease #Genetic Neurodegenerative Diseases #Mitochondrial Function and Pathology
paper · doi:10.1016/j.molcel.2025.09.030
openalex created_date 2025/10/21 · openalex publication_date 2025/10/21 · openalex updated_date 2026/07/31
Ribosome-associated protein quality control (RQC) protects cells against the toxic effects of faulty polypeptides produced by stalled ribosomes. However, mitochondria are vulnerable to C-terminal alanyl and threonyl (CAT)-tailed proteins that are generated in this process, and faulty nuclear-encoded mitochondrial proteins are handled by the recently discovered mitoRQC. Here, we performed a genome-wide screen in yeast to identify additional proteins involved in mitoRQC. We found that peptidyl-tRNA hydrolase 2 (Pth2), present in the mitochondrial outer membrane, influences aggregation of CAT-tailed proteins without majorly affecting the CAT-tailing process itself. Peptidyl-tRNA hydrolase activity is essential during this process, yet the activity of Pth2 can be substituted by another peptidyl-tRNA hydrolase upon proper localization. Our data suggest that Pth2 acts by modulating protein translocation and that the mitochondrial proteostasis network is relieved through increased access of CAT-tailed proteins to cytosolic chaperones. Other hits obtained in the screen show that, in general, delayed protein translocation protects mitochondria against toxic CAT-tailed proteins.