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Delayed protein translocation protects mitochondria against toxic CAT-tailed proteins

Nils Bertram1, Toshiaki Izawa2, Felix Thoma3

  • 1LMU Munich, Faculty of Biology, Cell Biology, 82152 Martinsried, Germany.

Molecular Cell
|October 21, 2025
PubMed

Insights

Mitochondria are protected from toxic CAT-tailed proteins by mitoRQC. The study identified peptidyl-tRNA hydrolase 2 (Pth2) as crucial for managing these faulty proteins by modulating translocation.

Area of Science:

  • Cellular biology
  • Mitochondrial function
  • Protein quality control

Background:

  • Ribosome-associated protein quality control (RQC) prevents cellular toxicity from stalled ribosomes.
  • Mitochondria are susceptible to C-terminal alanyl and threonyl (CAT)-tailed proteins, necessitating mitochondrial RQC (mitoRQC).
  • The mechanisms and components of mitoRQC are still being elucidated.

Purpose of the Study:

  • To identify novel proteins involved in the mitochondrial protein quality control (mitoRQC) pathway.
  • To investigate the role of peptidyl-tRNA hydrolase 2 (Pth2) in managing CAT-tailed proteins within mitochondria.
  • To understand how mitochondrial proteostasis is maintained against toxic protein aggregates.

Main Methods:

  • Genome-wide screening in yeast to identify proteins interacting with mitoRQC.
  • Biochemical assays to assess the activity of Pth2 and its impact on CAT-tailed protein aggregation.
  • Analysis of protein translocation and localization within mitochondria.

Main Results:

  • Peptidyl-tRNA hydrolase 2 (Pth2), located in the mitochondrial outer membrane, was identified as a key player in mitoRQC.
  • Pth2 influences the aggregation of CAT-tailed proteins without directly affecting the CAT-tailing process.
  • Pth2's function can be substituted by other peptidyl-tRNA hydrolases if correctly localized, and it modulates protein translocation.
  • Delayed protein translocation was found to protect mitochondria against toxic CAT-tailed proteins.

Conclusions:

  • Pth2 plays a significant role in mitochondrial proteostasis by influencing protein translocation and managing toxic CAT-tailed proteins.
  • The mitoRQC pathway utilizes Pth2 to mitigate the harmful effects of faulty polypeptides, thereby protecting mitochondrial integrity.
  • Altering protein translocation dynamics is a protective mechanism for mitochondria against aggregation-prone proteins.
Keywords:
RQCTOM complexcellular homeostasismitoRQCmitochondriapeptidyl-RNA hydrolaseprotein translocation

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