Mitochondrial protein import couples proteostasis failure to mitochondrial permeabilization
Sun, Z.; Holthusen, H.; Berndl, S.; Behnsen, A.; Schwojer, S. J.; Gobbato, G.; Sorensen, G.; Warscheid, B.; Sieber, S. A.; Hartl, F. U.; Hornung, V. · cell biology · 2026-09-06 · 原文
DOI：10.64898/2026.09.03.749044作者：11 位
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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1. 人话版
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.
2. 领域脉络
本文类目：cell biology，属于其所在研究脉络的最新进展。
3. 机制拆解
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.
4. 证据与数字
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.
5. 反例与边界
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.
6. 跨领域连接与意外收获
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7. 可复用方法
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