新辅助化疗（NACT）用于三阴性乳腺癌（TNBC）可在约45%的患者中根除肿瘤。不幸的是，具有显著残留癌负担的TNBC患者的无转移生存率和总体生存率较差。我们先前证明线粒体氧化磷酸化（OXPHOS）增加并且是残留TNBC细胞在NACT中存活的独特治疗依赖性。我们寻求研究增强对线粒体代谢依赖性的机制，了解此增强依赖于何种机制。线粒体是形态可塑的细胞器，可以在分裂和融合之间循环，以维持线粒体完整性和代谢稳态。线粒体结构对代谢产物的功能影响高度依赖于环境。几种传统的化疗药剂通常用于TNBC患者的新辅助治疗。通过比较传统化疗药物对线粒体的影响，我们发现DNA损伤剂增加了线粒体伸长，线粒体含量，经过TCA循环的葡萄糖通量和OXPHOS，而紫杉烷类药物则降低了线粒体伸长和OXPHOS。DNA损伤化疗药物对线粒体的影响依赖于线粒体内膜融合蛋白视神经萎缩1（OPA1）。此外，我们在残留TNBC的PDX模型中观察到了氧化磷酸化增强、OPA1蛋白水平和线粒体伸长。药物或基因干扰线粒体融合和分裂导致OXPHOS下降或增加，揭示出更长的线粒体有利于TNBC细胞的OXPHOS。使用TNBC细胞系和残余TNBC的PDX模型，我们发现顺序使用DNA损伤化疗药物，从而诱导线粒体融合和OXPHOS，然后使用MYLS22（一种特定的OPA1抑制剂），可以抑制线粒体融合和OXPHOS，并显着抑制残余肿瘤细胞的再生长。我们的数据表明，TNBC线粒体可以通过OPA1介导的线粒体融合来优化OXPHOS。这些发现可能为克服耐药性TNBC的线粒体适应提供机会。© 2023年。作者（们）在Springer Nature Limited独家许可下发表。

Neoadjuvant chemotherapy (NACT) used for triple negative breast cancer (TNBC) eradicates tumors in ~45% of patients. Unfortunately, TNBC patients with substantial residual cancer burden have poor metastasis free and overall survival rates. We previously demonstrated mitochondrial oxidative phosphorylation (OXPHOS) was elevated and was a unique therapeutic dependency of residual TNBC cells surviving NACT. We sought to investigate the mechanism underlying this enhanced reliance on mitochondrial metabolism. Mitochondria are morphologically plastic organelles that cycle between fission and fusion to maintain mitochondrial integrity and metabolic homeostasis. The functional impact of mitochondrial structure on metabolic output is highly context dependent. Several chemotherapy agents are conventionally used for neoadjuvant treatment of TNBC patients. Upon comparing mitochondrial effects of conventional chemotherapies, we found that DNA-damaging agents increased mitochondrial elongation, mitochondrial content, flux of glucose through the TCA cycle, and OXPHOS, whereas taxanes instead decreased mitochondrial elongation and OXPHOS. The mitochondrial effects of DNA-damaging chemotherapies were dependent on the mitochondrial inner membrane fusion protein optic atrophy 1 (OPA1). Further, we observed heightened OXPHOS, OPA1 protein levels, and mitochondrial elongation in an orthotopic patient-derived xenograft (PDX) model of residual TNBC. Pharmacologic or genetic disruption of mitochondrial fusion and fission resulted in decreased or increased OXPHOS, respectively, revealing longer mitochondria favor oxphos in TNBC cells. Using TNBC cell lines and an in vivo PDX model of residual TNBC, we found that sequential treatment with DNA-damaging chemotherapy, thus inducing mitochondrial fusion and OXPHOS, followed by MYLS22, a specific inhibitor of OPA1, was able to suppress mitochondrial fusion and OXPHOS and significantly inhibit regrowth of residual tumor cells. Our data suggest that TNBC mitochondria can optimize OXPHOS through OPA1-mediated mitochondrial fusion. These findings may provide an opportunity to overcome mitochondrial adaptations of chemoresistant TNBC.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.