AI Insight
This study reveals that protein folding failure can trigger mitochondrial damage and cell death through an unexpected mechanism involving mitochondrial protein import machinery. Researchers found that the compound Raptinal causes cell death not by directly damaging mitochondria, but by impairing protein folding, which then overloads the TIM23 protein import system and leads to mitochondrial membrane breakdown independently of the usual BCL-2 family proteins. Blocking the TIM23 import pathway prevented mitochondrial damage during proteostasis failure, identifying protein import regulation as a key determinant of mitochondrial health under cellular stress.
Why it matters
These findings identify a new pathway connecting protein misfolding to mitochondrial dysfunction, which is relevant to understanding neurodegenerative diseases, aging, and other conditions where both proteostasis failure and mitochondrial damage occur. The discovery that modulating mitochondrial import machinery can protect against proteotoxic stress suggests potential therapeutic targets for diseases involving protein aggregation.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.
Source: Mitochondrial protein import couples proteostasis failure to mitochondrial permeabilization