Cell-to-Cell stochastic fluctuations in apoptotic signaling can decide between life and death

TL;DR

This study uses stochastic simulations to reveal how cell-to-cell fluctuations in apoptotic signaling influence cell fate decisions, especially under weak death signals, highlighting the role of stochasticity in apoptosis pathways.

Contribution

Developed a Monte Carlo-based stochastic model to characterize signaling behaviors and fluctuations in apoptotic pathways, revealing bimodal caspase-3 activation distributions.

Findings

Type 2 mitochondrial pathway dominates under weak death signals.

Signaling in the pathway is stochastic with cell-to-cell variability.

Bimodal distribution of caspase-3 activation indicates stochastic behavior.

Abstract

Apoptosis, or genetically programmed cell death, is a crucial cellular process that maintains the balance between life and death in cells. The precise molecular mechanism of apoptosis signaling and how these two pathways are differentially activated under distinct apoptotic stimuli is poorly understood. We developed a Monte Carlo-based stochastic simulation model that can characterize distinct signaling behaviors in the two major pathways of apoptotic signaling using a novel probability distribution-based approach. Specifically, we show that for a weak death signal, such as low levels of death ligand Fas (CD95) binding or under stress conditions, the type 2 mitochondrial pathway dominates apoptotic signaling. Our results also show signaling in the type 2 pathway is stochastic, where the population average over many cells does not capture the cell-to-cell fluctuations in the time course (~1 - 10 hours) of downstream caspase-3 activation. On the contrary, the probability distribution of caspase-3 activation for the mitochondrial pathway shows a distinct bimodal behavior that can be used to characterize the stochastic signaling in type 2 apoptosis. Interestingly, such stochastic fluctuations in apoptosis signaling happen even in the presence of large numbers of signaling molecules. In a fluctuating environment, such stochasticity in the timecourse of caspase-3 activation may be an adaptive mechanism for allowing a competing survival signal to win over a weak death trigger before the critical cell fate decision is made and thus minimizes the risk of pathologies.