TY - JOUR
T1 - Apoptotic priming is defined by the dynamic exchange of Bcl-2 proteins between mitochondria and cytosol.
AU - King, Louise
AU - Rodriguez-Enriquez, Ricardo
AU - Pedley, Robert
AU - Mellor, Charlotte
AU - Wang, Pengbo
AU - Zindy, Egor
AU - White, Michael
AU - Brennan, Keith
AU - Gilmore, Andrew
PY - 2022/4/22
Y1 - 2022/4/22
N2 - Apoptosis is regulated by interactions between the BH3-only and multidomain 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.
AB - Apoptosis is regulated by interactions between the BH3-only and multidomain 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.
M3 - Article
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
ER -