Mitochondrial stress-induced protein carboxyl-terminal alanine threonine tailing (msiCAT-tailing) facilitates glioblastoma tumorigenesis through the modulation of mitochondrial functions.

The rapid and sustained proliferation of cancer cells necessitates increased protein production, which, along with their disrupted metabolism, elevates the likelihood of translation errors. Ribosome-associated quality control (RQC), a recently identified mechanism, mitigates ribosome collisions resulting from frequent translation stalls. However, the precise pathophysiological role of the RQC pathway in oncogenesis remains ambiguous. Our research centered on the pathogenic implications of mitochondrial stress-induced protein carboxyl-terminal alanine and threonine tailing (msiCAT-tailing), a specific RQC response to translational arrest on the outer mitochondrial membrane, in glioblastoma (GBM). The presence of msiCAT-tailed mitochondrial proteins was observed commonly in glioblastoma stem cells (GSCs). Exogenous introduction of mitochondrial ATP synthase F1 subunit alpha (ATP5α) protein with artificial CAT-tail mimicking sequences enhanced mitochondrial membrane potential (ΔΨm) and inhibited mitochondrial permeability transition pore (MPTP) formation. These alterations in mitochondrial characteristics provided resistance to staurosporine (STS)-induced apoptosis in GBM cells. Consequently, msiCAT-tailing can foster cell survival and migration, whereas blocking msiCAT-tailing via genetic or pharmacological intervention can impede GBM cell overgrowth.