Abstract
The rapid, typically all-or-none process of mitochondrial outer membrane permeabilization (MOMP) constitutes a primary cell death decision that is controlled by the Bcl-2 family interactome. However, how strict all-or-none MOMP decisions are governed by and emanate from the dynamic interplay of pro- and antiapoptotic Bcl-2 family members remains incompletely understood. In particular, it is unclear to which extent the shuttling of Bcl-2 family species between lipid and aqueous phases contributes to regulating MOMP sensitivity. Here, we studied the interplay of tBid, Bax, and Bcl-xL, using a combined approach of deterministic mathematical modeling and retrospective as well as prospective experimental testing of model predictions. Systems modeling of the tBid–Bax interplay and their fluxes between cytosol and mitochondrial membranes reproduced experimental data on tBid-triggered Bax activation and oligomerization highly accurately. Extending these studies to analyze the cell-protective role of Bcl-xL strikingly revealed that the activity of Bcl-xL to retrotranslocate activated Bax from membranes back into the cytosol is essential to reproduce or correctly predict experimental outcomes. These included the potency of Bcl-xL in suppressing Bax oligomerization, its role in limiting Bax membrane recruitment, the resistance threshold to low concentrations of MOMP triggers as well as a response potentiaton arising from combinations of tBid and sensitizer BH3-only peptides. Importantly, retrotranslocation activity of Bcl-xL is necessary to strictly separate conditions of MOMP competency and resistance. Our results therefore identify Bax retrotranslocation by Bcl-xL as an indispensable component of the molecular switch by which Bcl-2 family members govern cellular death decisions.
Highlights
Pro- and antiapoptotic members of the Bcl-2 (B-cell lymphoma 2) protein family gather signals from stress sensing pathways and regulate the mitochondrial pathway of apoptosis[1,2]
We initially developed a core mathematical model of the truncated Bid (tBid)–Bax interplay at and within membranes to study if membrane recruitment, activation, and oligomerization of Bax, leading to mitochondrial outer membrane permeabilization (MOMP), can be simulated authentically
The activator BH3-only protein tBid was implemented to promote the insertion of monomeric Bax into the outer mitochondrial membrane[22] (Fig. 1a)
Summary
Pro- and antiapoptotic members of the Bcl-2 (B-cell lymphoma 2) protein family gather signals from stress sensing pathways and regulate the mitochondrial pathway of apoptosis[1,2]. We studied the regulation of MOMP by the interplay of tBid, Bax, and Bcl-xL at and within membranes, using a combined approach of deterministic mathematical modeling and experimental validation of model predictions.
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