线粒体蛋白翻译支持化疗难治性三阴性乳腺癌的代谢重塑

Nearly 45% of patients with triple negative breast cancer (TNBC) treated with chemo-immunotherapy have residual cancer burden, which is associated with relapse and mortality. Previously, our group reported that TNBCs rely heavily on mitochondrial structural and functional adaptations to survive treatment (PMIDs 30996079, 36813854). Additionally, mitochondrial translation-related proteomic profiles of TNBC patients (n=55, PMID 36001024) and orthotopic PDX tumors (n=42, PMID 39713418) reveal a significant association with resistance to carboplatin (CRB), docetaxel (DTX), or their combination. Furthermore, on-treatment biopsies were collected from a subset of patients, and mitochondrial translation proteomic signatures were significantly elevated relative to their matched pre-treatment counterparts. Leading-edge proteins in those pathways included 30 mitoribosome proteins and the accessory protein Oxidase (Cytochrome C) Assembly 1-Like (OXA1L). OXA1L plays two crucial roles in the mitochondria: 1) it promotes translation termination for the 13 mtDNA-encoded mitochondrial respiratory chain (MRC) proteins, and 2) it aids in inner mitochondrial membrane insertion of mtDNA- and nDNA-encoded MRC proteins. Therefore, we hypothesized that mitochondrial translation, supported by OXA1L, is critical for maintaining mitochondrial function and chemoresistance in TNBC. Knock-down (KD) of OXA1L in TNBC cells significantly reduced MRC protein levels, mitochondrial ‘respirasome' supercomplex formation, and oxidative phosphorylation (oxphos). Notably, the characteristic elevation of oxphos in ‘residual' cells surviving CRB treatment was abolished by the KD. Concomitantly, OXA1L KD cells exhibited significantly improved CRB sensitivity relative to control cells. These results underscore the significance of OXA1L in MRC assembly and function in TNBC, as well as its role in supporting chemoresistance. Though there are no existing inhibitors of OXA1L, we tested the translational potential of our findings by leveraging the mitochondria's bacterial ancestry through repurposing FDA-approved antibiotics to inhibit mitochondrial translation (PMID 25625193). We demonstrated inhibition of mitochondrial translation, MRC protein production, respirasome formation, and oxphos with low-dose tigecycline (TIG) treatment in TNBC cells. While we observed minimal toxicity to TNBC cells from TIG as a single agent, we found a significant enhancement of sensitivity to conventional chemotherapies, both in vitro and in vivo, in a PDX. In summary, our data reveal the vital role of mitochondrial translation for the metabolic adaptation and survival of chemo-refractory TNBC. Moreover, these data provide evidence that disrupting MRC assembly by inhibiting mitochondrial translation may be a promising approach to overcome mitochondrial vulnerabilities in chemo-refractory TNBC.