Abstract
Chemoresistance poses a critical obstacle in bladder cancer (BCa) treatment, and effective interventions are currently limited. Elevated oxidative phosphorylation (OXPHOS) has been linked to cancer stemness, a determinant of chemoresistance. However, the mechanisms underlying increased OXPHOS during cancer cell chemoresistance remain unclear. This study revealed that the mitochondrial translational activator of cytochrome oxidase subunit 1 (TACO1) is linked to stemness and cisplatin resistance in BCa cells. Mechanistically, mitochondrial TACO1 enhances the translation of the mitochondrial cytochrome c oxidase I (MTCO1), promoting mitochondrial reactive oxygen species (mtROS) by upregulating OXPHOS, consequently driving cancer stemness and cisplatin resistance. Intriguingly, the mitochondrial translocation of TACO1 is mediated by the heat shock protein 90 β (HSP90β), a process that requires circFOXK2 as a scaffold for the TACO1-HSP90β interaction. The mutations at the binding sites of TACO1-circFOXK2-HSP90β disturb the ternary complex and inhibit cancer stemness and cisplatin resistance in BCa cells by suppressing the MTCO1/OXPHOS/mtROS axis. Clinically, BCa patients with increased mitochondrial TACO1 expression respond poorly to cisplatin treatment. This study elucidates the mechanisms by which TACO1 promotes BCa stemness and cisplatin resistance, providing a potential target for mitigating cisplatin resistance for BCa and a biomarker for predicting cisplatin response.