Proteostasis Network Relieved through Increased Access of CAT-tailed Proteins to Cytosolic Chaperones

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Researchers at the Faculty of Medicine have conducted a genome-wide screen in yeast to identify additional proteins involved in mitoRQC, a process that protects mitochondria against toxic proteins. The study found that peptidyl-tRNA hydrolase 2 (Pth2), present in the mitochondrial outer membrane, influences aggregation of CAT-tailed proteins without affecting the CAT-tailing process itself. Pth2 acts by modulating protein translocation, allowing CAT-tailed proteins to access cytosolic chaperones, thus relieving the mitochondrial proteostasis network.

Key Takeaways:

  • Ribosome-associated protein quality control (RQC) protects cells against faulty polypeptides produced by stalled ribosomes, but mitochondria are vulnerable to C-terminal alanyl and threonyl (CAT)-tailed proteins.
  • Peptidyl-tRNA hydrolase 2 (Pth2) influences aggregation of CAT-tailed proteins in the mitochondrial outer membrane.
  • Pth2 modulates protein translocation, allowing CAT-tailed proteins to access cytosolic chaperones, relieving the mitochondrial proteostasis network.
  • Delayed protein translocation protects mitochondria against toxic CAT-tailed proteins.
  • The research suggests that the mitochondrial proteostasis network is relieved through increased access of CAT-tailed proteins to cytosolic chaperones.
  • Peptidyl-tRNA hydrolase activity is essential during the process of protein translocation, but can be substituted by another peptidyl-tRNA hydrolase upon proper localization.
  • The study found that Pth2 acts by modulating protein translocation and that delayed protein translocation protects mitochondria against toxic CAT-tailed proteins.
  • Other hits obtained in the screen show that, in general, delayed protein translocation is beneficial for mitochondrial health.
  • The research has identified a new mechanism of mitochondrial proteostasis, involving the regulation of protein translocation and the activity of Pth2.

Statistics:

  • 2025: The year in which the research was published.
  • Molecular Cell: The journal in which the research was published.
  • 50 Hampshire St, Floor 5, Cambridge, MA 02139, USA: The address of the publisher of the journal Molecular Cell.
  • Cell Press: The publisher of the journal Molecular Cell.
  • Elsevier: The publisher of the journal Molecular Cell.
  • Faculty of Medicine: The institution affiliated with the research.
  • Martinsried, Germany: The location of the Faculty of Medicine.
  • Peptidyl-tRNA hydrolase 2 (Pth2): The protein studied in the research.
  • Mitochondria: The organelle studied in the research.
  • CAT-tailed proteins: The proteins studied in the research.
  • Cytosolic chaperones: The proteins involved in the process of protein translocation.
  • Genome-wide screen: The experimental approach used in the research.

Sources:

  • NewsRx. Findings from Faculty of Medicine Provides New Data about Proteins (Delayed protein translocation protects mitochondria against toxic CAT-tailed proteins). Life Science Weekly. November 4, 2025; p 896.
  • Delayed protein translocation protects mitochondria against toxic CAT-tailed proteins. Molecular Cell, 2025.
  • Molecular Cell. 2025. Molecular Cell can be contacted at: Cell Press, 50 Hampshire St, Floor 5, Cambridge, MA 02139, USA.