Apoptotic priming is defined by the dynamic exchange of Bcl-2 proteins between mitochondria and cytosol

Apoptosis is regulated by interactions between the BH3-only and multi-domain Bcl-2 family proteins. These interactions are integrated on the outer mitochondrial membrane (OMM) where they set the threshold for apoptosis, known as mitochondrial priming. However, how mitochondrial priming is controlled at the level of single cells remains unclear. Retrotranslocation of Bcl-XL has been proposed as one mechanism, removing pro-apoptotic Bcl-2 proteins from the OMM, thus reducing priming. Contrary to this view, we now show that Bcl-XL retrotranslocation is inhibited by binding to its BH3-only partners, resulting in accumulation of these protein complexes on mitochondria. We find that Bcl-XL retrotranslocation dynamics are tightly coupled to mitochondrial priming. Quantifying these dynamics indicates the heterogeneity in priming between cells within a population and predicts how they subsequently respond to a pro-apoptotic signal.

Automated summary

Mitochondrial priming, an important process in regulating cell apoptosis, is closely related to the retrotranslocation dynamics of Bcl-XL. This study reveals that the binding of Bcl-XL to its BH3-only partners inhibits its retrotranslocation, leading to accumulation of protein complexes carrying priming on mitochondria. Additionally, heterogeneity in priming between cells within a population is found, which predicts their subsequent response to pro-apoptotic signals.