Mitochondrial protein import couples proteostasis failure to mitochondrial permeabilization
- 1Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
Abstract
Proteostasis failure is a hallmark of stress and disease, yet how it compromises mitochondrial integrity remains unclear. Here, we identify mitochondrial protein import as a critical pathway linking proteostasis failure to mitochondrial injury. We show that Raptinal, previously characterized as a rapid inducer of apoptosis, impairs the folding of newly synthesized proteins rather than directly disrupting mitochondrial membranes. The resulting proteotoxic stress drives mitochondrial outer membrane permeabilization and intrinsic apoptosis independently of BCL-2 family pore-forming proteins. VBIT4, a compound commonly used to maintain mitochondrial integrity, inhibited this pathway, and chemical proteomics with a photoaffinity analogue implicated the TIM23 import machinery. Genetic or pharmacological inhibition of the TIM23-PAM axis suppressed mitochondrial permeabilization without affecting canonical BAX-BAK-dependent apoptosis. These findings establish that mitochondrial protein import couples translation-associated proteotoxic stress to mitochondrial injury and identify regulation of import flux as a determinant of mitochondrial integrity during proteostasis failure.
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BibTeX
@misc{sun2026mitochondrial,
title = {{Mitochondrial protein import couples proteostasis failure to mitochondrial permeabilization}},
author = {Z. Sun and H. Holthusen and S. Berndl and A. Behnsen and S. J. Schwojer and G. Gobbato and G. Sorensen and B. Warscheid and S. A. Sieber and F. U. Hartl and V. Hornung},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.749044},
url = {https://www.biorxiv.org/content/10.64898/2026.09.03.749044v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Mitochondrial protein import couples proteostasis failure to mitochondrial permeabilization
AU - Z. Sun
AU - H. Holthusen
AU - S. Berndl
AU - A. Behnsen
AU - S. J. Schwojer
AU - G. Gobbato
AU - G. Sorensen
AU - B. Warscheid
AU - S. A. Sieber
AU - F. U. Hartl
AU - V. Hornung
PY - 2026
DA - 2026/09/03
PB - bioRxiv
DO - 10.64898/2026.09.03.749044
UR - https://www.biorxiv.org/content/10.64898/2026.09.03.749044v1
AB - Proteostasis failure is a hallmark of stress and disease, yet how it compromises mitochondrial integrity remains unclear. Here, we identify mitochondrial protein import as a critical pathway linking proteostasis failure to mitochondrial injury. We show that Raptinal, previously characterized as a rapid inducer of apoptosis, impairs the folding of newly synthesized proteins rather than directly disrupting mitochondrial membranes. The resulting proteotoxic stress drives mitochondrial outer membrane permeabilization and intrinsic apoptosis independently of BCL-2 family pore-forming proteins. VBIT4, a compound commonly used to maintain mitochondrial integrity, inhibited this pathway, and chemical proteomics with a photoaffinity analogue implicated the TIM23 import machinery. Genetic or pharmacological inhibition of the TIM23-PAM axis suppressed mitochondrial permeabilization without affecting canonical BAX-BAK-dependent apoptosis. These findings establish that mitochondrial protein import couples translation-associated proteotoxic stress to mitochondrial injury and identify regulation of import flux as a determinant of mitochondrial integrity during proteostasis failure.
ER -