Translation stalling induced mitochondrial entrapment of ribosomal quality control related proteins offers cancer cell vulnerability

TL;DR

This study reveals that mitochondrial entrapment of ribosomal quality control proteins, like ABCE1, can make cancer cells vulnerable to treatment.

Contribution

The paper introduces stalling-induced mitochondrial stress (SIMS) as a novel mechanism linking ribosomal quality control to cancer cell vulnerability.

Findings

ABCE1 and ZNF598 are positively correlated with high-grade bladder cancer.

Translational stalling increases mitochondrial localization of RQC proteins, reducing their cytosolic availability.

Cancer stem cells show increased ABCE1 expression, contributing to resistance against mitochondrial dysfunction.

Abstract

Ribosome-associated quality control (RQC) monitors ribosomes for aberrant translation. While the role of RQC in neurodegenerative disease is beginning to be appreciated, its involvement in cancer is understudied. Here, we show a positive correlation between RQC proteins ABCE1 and ZNF598 and high-grade muscle-invasive bladder cancer. Translational stalling by the inhibitor emetine (EME) leads to increased mitochondrial localization of RQC factors including ABCE1, ZNF598, and NEMF, which are continuously imported into mitochondria facilitated by increased mitochondrial membrane potential caused by EME. This reduces the availability of these factors in the cytosol, compromising the effectiveness of RQC in handling stalled ribosomes in the cytosol and those associated with the mitochondrial outer membrane (MOM). Imported RQC factors form aggregates inside the mitochondria in a process we term stalling-induced mitochondrial stress (SIMS). ABCE1 plays a crucial role in maintaining mitochondrial health during SIMS. Notably, cancer stem cells (CSCs) exhibit increased expression of ABCE1 and consequently are more resistant to EME-induced mitochondrial dysfunction. This points to a potential mechanism of drug resistance by CSCs. Our study highlights the significance of mitochondrial entrapment of RQC factors such as ABCE1 in determining the fate of cancer cells versus CSCs. Targeting ABCE1 or other RQC factors in translational inhibition cancer therapy may help overcome drug resistance.

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