Mitochondria are morphologically plastic organelles that cycle between fission and fusion to maintain mitochondrial integrity and metabolic homeostasis. We found that DNA-damaging agents increased mitochondrial fusion, mitochondrial content, flux of glucose through the TCA cycle, and OXPHOS, whereas taxanes instead decreased mitochondrial fusion and OXPHOS. These events are mediated by the mitochondrial inner membrane fusion protein optic atrophy 1 (OPA1). 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 inhibited residual tumor regrowth. Our findings suggest that TNBC mitochondria can optimize OXPHOS through modulation of mitochondrial structure. This may provide an opportunity to therapeutically target mitochondrial adaptations of chemoresistant TNBC.