IjBa inhibits apoptosis at the outer mitochondrial membrane independently of NF-jB retention

IjBa resides in the cytosol where it retains the inducible transcription factor NF-jB. We show that IjBa also localises to the outer mitochondrial membrane (OMM) to inhibit apoptosis. This effect is especially pronounced in tumour cells with constitutively active NF-jB that accumulate high amounts of mitochondrial IjBa as a NF-jB target gene. 3T3 IjBa / cells also become protected from apoptosis when IjBa is specifically reconstituted at the OMM. Using various IjBa mutants, we demonstrate that apoptosis inhibition and NF-jB inhibition can be functionally and structurally separated. At mitochondria, IjBa stabilises the complex of VDAC1 and hexokinase II (HKII), thereby preventing Bax recruitment to VDAC1 and the release of cytochrome c for apoptosis induction. When IjBa is reduced in tumour cells with constitutively active NF-jB, they show an enhanced response to anticancer treatment in an in vivo xenograft tumour model. Our results reveal the unexpected activity of IjBa in guarding the integrity of the OMM against apoptosis induction and open possibilities for more specific interference in tumours with deregulated NF-jB.