Deciphering Bax Dynamics: Regulation, Retrotranslocation, and Mitochondrial Interplay in the Commitment to Apoptosis: A Narrative Review.

Background: The apoptotic pathway mediated by mitochondria depends on the activation of pro-apoptotic Bcl-2 proteins Bax and Bak. When they permeabilize the outer mitochondrial membrane (OMM), mitochondrial dysfunction occurs, leading to caspase activation. A recent study proposed that Bax accumulation on mitochondria increases apoptotic susceptibility, with adhesion-initiated signals regulating Bax. When adhesion signaling is inhibited, Bax translocates to the OMM, undergoes conformational change, and forms complexes that create pores. Although MOMP is well studied, mechanisms regulating Bax shuttling, non-canonical partners, and mitochondrial dynamics remain poorly understood. Aims: This review aims to provide insights by discussing the mechanisms through which Bax regulates its mitochondrial targeting, the mitochondrial dynamics associated with Bax translocation, and their influence to apoptosis. Understanding these processes could reveal new insights into the decision-making checkpoints that determine cell death. Methods: A comprehensive literature search was conducted across scientific databases for peer-reviewed publications up to 2025. Search terms included Results: Recent evidence shows that Bax continuously retrotranslocates from mitochondria to the cytosol under survival conditions, a process driven by anti-apoptotic Bcl-2 proteins. When adhesion signaling or other survival cues are inhibited, this cycle is disrupted, leading to Bax accumulation on mitochondria, its oligomerization, and the onset of MOMP. Several mitochondrial proteins, including Drp1, MAVS, OCIAD1, PTPN1, and AKAP1, have also been linked to a mitochondrial interaction network that influences Bax localization and retrotranslocation. Proximity-labeling approaches such as BioID are further identifying new proteins that may regulate Bax's mitochondrial targeting and apoptotic priming. Conclusion: The mechanisms driving Bax accumulation on mitochondria and its retrotranslocation remain unclear, especially the role of mitochondrial proteins. Evidence suggests mitochondrial interaction networks influence Bax and Bak regulation. Further research is needed to define how these networks integrate with the Bcl-2 interactome to shape apoptotic decisions.