Nur77 inhibits mitochondrial excessive fragmentation through mutated p53 L194F in T47D breast cancer cells.

Nur77 is an orphan nuclear receptor for which no endogenous ligand has yet been identified. It has been demonstrated that there is aberrant expression or dysfunction of nur77 in breast cancer (BC), however, its role in different types of breast cancer remains contentious. Despite mounting evidence that Nur77 exerts influence over mitochondrial dynamics, including fission, fusion and mitophagy of mitochondria in diverse systems, the role and mechanism of mitochondrial dynamics regulated by Nur77 in tumor cells remain opaque. In the present study, significant differences in Nur77 levels were observed in various BC cell types, particularly in the Luminal A-type cell lines MCF-7 and T47D. Nur77 was more highly expressed in T47D cells with the p53 L194F mutation and significantly promoted the growth of T47D cells. In T47D cells, the knockout of Nur77 unequivocally disrupted mitochondrial function, inducing excessive mitochondrial fragmentation and inactivating mitophagy. Further mechanistic studies demonstrated that only the mutant p53 L194F protein in T47D regulated p-Drp1-S616 in comparison to the wild-type p53 protein in MCF-7 cells. Nur77 up-regulated p53 L194F expression at the transcriptional level and exerted a stronger effect on the interaction of Drp1 with mutant p53 L194F. These results suggest that the Nur77/p53 L194F/ mitofission axis may be involved in the mitochondrial homeostasis of specific types of BC cells to maintain BC cell growth. The discovery of this axis provides an important experimental basis for the fine classification of Luminal A BC and the identification of new therapeutic targets.