ABSTRACT Triple‐negative breast cancer (TNBC) has a high rate of metastasis and recurrence, and lacks targeted and accurate treatment strategies. Mitochondrial metabolic reprogramming is a potential marker for cancer therapy, and mitochondrial metabolic changes mediated by mitochondrial dynamics have been used to inhibit the metastatic potential of various cancers. However, how the epithelial–mesenchymal transition (EMT) and metabolism mediated by the different homologous mitochondrial fusion proteins MFN1/2 affect breast cancer migration and invasion, and their compensatory effects have not been studied. Herein, we demonstrated that MFN1 knockdown significantly inhibited the mitochondrial membrane potential and enhanced the intracellular ATP content, proliferation, migration, invasion, and tumorigenic ability of BT20 by enhancing glycolysis. Disturbing MFN2 had a similar effect on the mitochondrial metabolic performance of BT20 as MFN1, but showed no significant effect on the proliferation, migration, and invasion of BT20. MFN1 knockdown promoted the migration and invasion of BT20 by inducing mitochondrial division and EMT. Furthermore, we discovered that MFN2 could, to a certain extent, reverse the effects of MFN1 knockdown on mitochondrial metabolism, proliferation, EMT, migration, and invasion efficiency in BT20 through the compensation experiments. Meanwhile, Mdivi‐1 could reverse the EMT changes and cell morphology caused by MFN1 knockdown via inhibiting mitochondrial fission in BT20. 2DG could also reverse these changes by inhibiting glycolysis, and this process is mediated by enhancing AMPK, MAPK/ERK signaling, and inhibiting PI3K/Akt signaling. This study provides innovative ideas for the targeted regulation of mitochondrial fusion in TNBC therapy.
Zhang et al. (Sat,) studied this question.
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