Msp1-dependent extraction promotes ubiquitylation of translocation-stalled mitochondrial precursor proteins
- 1Institute of Biochemistry and Molecular Biology, University Hospital Bonn, University of Bonn, 53115 Bonn, Germany
Abstract
The translocase of the outer membrane (TOM complex) imports more than 1,000 proteins into mitochondria. Clogging of the TOM pore with a precursor protein causes proteotoxic stress and eventually cell death. Two quality control pathways remove translocation-stalled precursor proteins. In the mitochondrial protein translocation-associated degradation (mitoTAD), Ubx2 recruits the cytosolic AAA-ATPase Cdc48 to clear precursor proteins from the TOM complex. In the mitochondrial compromised protein import response (mitoCPR), the stress-induced Cis1 recruits the AAA-ATPase Msp1 to Tom70. The role of Msp1 for the removal of mitochondrial precursor proteins remains unknown. Here, we demonstrate that parallel loss of Msp1 and Ubx2 strongly affects removal of precursor proteins and cell viability. Msp1 and Ubx2 bind independently of import stress and Cis1 to the TOM complex to remove a large variety of precursor proteins. Msp1-dependent extraction promotes ubiquitylation of precursor proteins, which in turn allows Ubx2-recruited Cdc48 to transfer the substrates to proteasomal degradation. We conclude that two AAA-ATPases cooperate in mitochondrial precursor quality control. Msp1-dependent extraction from the TOM complex facilitates precursor ubiquitylation and Cdc48-mediated transfer to proteasomal degradation.
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BibTeX
@misc{engelke2026msp1dependent,
title = {{Msp1-dependent extraction promotes ubiquitylation of translocation-stalled mitochondrial precursor proteins}},
author = {J. Engelke and N. Occhipinti and L. Pitzke and K. Ritzenhofen and R. Hardt and M. Sylvester and E. Scifo and F. den Brave and T. Becker},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.754956},
url = {https://www.biorxiv.org/content/10.64898/2026.09.28.754956v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Msp1-dependent extraction promotes ubiquitylation of translocation-stalled mitochondrial precursor proteins
AU - J. Engelke
AU - N. Occhipinti
AU - L. Pitzke
AU - K. Ritzenhofen
AU - R. Hardt
AU - M. Sylvester
AU - E. Scifo
AU - F. den Brave
AU - T. Becker
PY - 2026
DA - 2026/09/28
PB - bioRxiv
DO - 10.64898/2026.09.28.754956
UR - https://www.biorxiv.org/content/10.64898/2026.09.28.754956v1
AB - The translocase of the outer membrane (TOM complex) imports more than 1,000 proteins into mitochondria. Clogging of the TOM pore with a precursor protein causes proteotoxic stress and eventually cell death. Two quality control pathways remove translocation-stalled precursor proteins. In the mitochondrial protein translocation-associated degradation (mitoTAD), Ubx2 recruits the cytosolic AAA-ATPase Cdc48 to clear precursor proteins from the TOM complex. In the mitochondrial compromised protein import response (mitoCPR), the stress-induced Cis1 recruits the AAA-ATPase Msp1 to Tom70. The role of Msp1 for the removal of mitochondrial precursor proteins remains unknown. Here, we demonstrate that parallel loss of Msp1 and Ubx2 strongly affects removal of precursor proteins and cell viability. Msp1 and Ubx2 bind independently of import stress and Cis1 to the TOM complex to remove a large variety of precursor proteins. Msp1-dependent extraction promotes ubiquitylation of precursor proteins, which in turn allows Ubx2-recruited Cdc48 to transfer the substrates to proteasomal degradation. We conclude that two AAA-ATPases cooperate in mitochondrial precursor quality control. Msp1-dependent extraction from the TOM complex facilitates precursor ubiquitylation and Cdc48-mediated transfer to proteasomal degradation.
ER -