Mitochondrial protein import couples proteostasis failure to mitochondrial permeabilization
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…
Proteostasis failure, a common trait of stress and disease, has long puzzled scientists regarding its impact on mitochondrial integrity. A new study sheds light on this connection by pinpointing mitochondrial protein import as a crucial pathway that links proteostasis failure to mitochondrial damage. Researchers discovered that Raptinal, a substance known to trigger rapid apoptosis, does not directly harm mitochondrial membranes but rather disrupts the folding of newly synthesized proteins.
This protein folding issue then triggers a series of events, leading to mitochondrial outer membrane permeabilization and intrinsic apoptosis, independent of the BCL-2 family pore-forming proteins. The study also found that the compound VBIT4 can maintain mitochondrial integrity by inhibiting this pathway, with chemical proteomics revealing the involvement of the TIM23 import machinery.
Importantly, genetic or pharmacological inhibition of the TIM23-PAM axis effectively suppressed mitochondrial permeabilization without influencing the typical BAX-BAK-dependent apoptosis. This groundbreaking research establishes a direct link between mitochondrial protein import and translation-induced proteotoxic stress, highlighting the importance of regulating import flux in maintaining mitochondrial integrity during proteostasis failure.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
