Metabolic adaptation to IMMT deficiency through the ATF6-PPARγ axis is contingent on TP53 mutation status in breast cancer.

Mitochondrial dysfunction and the corresponding metabolic reprogramming have been established as critical drivers of tumor progression; nevertheless, the specific molecular mechanisms have not yet been fully elucidated. In this study, we reveal that ablation of inner mitochondrial membrane protein (IMMT), a key architectural component of mitochondrial cristae, induces concurrent mitochondrial and endoplasmic reticulum stress (ERS), which selectively activates the ATF6-mediated unfolded protein response (UPR) to drive breast cancer (BC) cell proliferation. Mechanistically, IMMT loss promotes ATF6α-ATF6β heterodimer formation, whereby ATF6α stabilizes ATF6β protein, enabling ATF6β to engage PPARγ through direct physical interaction and orchestrate redox homeostasis remodeling that sustains tumor cell proliferation. Notably, we discovered that this compensatory stress adaptation is context-dependent, manifesting specifically in TP53-mutant tumors, but not in their wild-type counterparts, and targeted disruption of the ATF6β-PPARγ signaling axis effectively abrogates the oncogenic effects induced by IMMT-KO. Our work uncovers a previously unrecognized adaptive axis linking chronic mitochondrial dysfunction to redox control in BC and establishes ATF6β as a critical effector that partners with PPARγ under stress-a functional role distinct from its classical regulatory relationship with ATF6α. These findings provide a theoretical foundation for precision therapeutic strategies targeting vulnerabilities in the stress adaptation pathway of BC.