Abstract
BackgroundMitochondria are key regulators of apoptosis. In response to stress, BH3-only proteins activate pro-apoptotic Bcl2 family proteins Bax and Bak, which induce mitochondrial outer membrane permeabilization (MOMP). While the large-scale mitochondrial release of pro-apoptotic proteins activates caspase-dependent cell death, a limited release results in sub-lethal caspase activation which promotes tumorigenesis. Mitochondrial autophagy (mitophagy) targets dysfunctional mitochondria for degradation by lysosomes, and undergoes extensive crosstalk with apoptosis signaling, but its influence on apoptosis remains undetermined. The BH3-only protein Bnip3 integrates apoptosis and mitophagy signaling at different signaling domains. Bnip3 inhibits pro-survival Bcl2 members via its BH3 domain and activates mitophagy through its LC3 Interacting Region (LIR), which is responsible for binding to autophagosomes. Previously, we have shown that Bnip3-activated mitophagy prior to apoptosis induction can reduce mitochondrial activation of caspases, suggesting that a reduction to mitochondrial levels may be pro-survival. An outstanding question is whether organelle dynamics and/or recently discovered subcellular variations of protein levels responsible for both MOMP sensitivity and crosstalk between apoptosis and mitophagy can influence the cellular apoptosis decision event. To that end, here we undertook a systems biology analysis of mitophagy-apoptosis crosstalk at the level of cellular mitochondrial populations.ResultsBased on experimental findings, we developed a multi-scale, hybrid model with an individually adaptive mitochondrial population, whose actions are determined by protein levels, embedded in an agent-based model (ABM) for simulating subcellular dynamics and local feedback via reactive oxygen species signaling. Our model, supported by experimental evidence, identified an emergent regulatory structure within canonical apoptosis signaling. We show that the extent of mitophagy is determined by levels and spatial localization of autophagy capacity, and subcellular mitochondrial protein heterogeneities. Our model identifies mechanisms and conditions that alter the mitophagy decision within mitochondrial subpopulations to an extent sufficient to shape cellular outcome to apoptotic stimuli.ConclusionOverall, our modeling approach provides means to suggest new experiments and implement findings at multiple scales in order to understand how network topologies and subcellular heterogeneities can influence signaling events at individual organelle level, and hence, determine the emergence of heterogeneity in cellular decisions due the actions of the collective intra-cellular population.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-015-0115-9) contains supplementary material, which is available to authorized users.
Highlights
Mitophagy and apoptosis pathway behavior for single mitochondrion We first developed an ordinary differential equation (ODE) model for a single mitochondrion based on experimental findings in order to evaluate dynamic behavior stemming from Bnip3mediated mitophagy and apoptosis signaling (Fig. 1a, Additional file 1: Figure S1)
A critical assumption of our ODE model is that LIRmediated mitophagy and BH3-mediated Bax activation are branched pathways, with Bcl2/adenovirus E1B kDa protein-interacting protein 3 (Bnip3) acting as an initiating signaling hub including multiple points of crosstalk
We focused our model on Bnip3, which is a sensitizer to BH3-only protein [40], an inducer [46] and sensor of reactive oxidative species (ROS) [43], and crucially, contains a phosphorylation-regulated LC3 Interacting Region (LIR) domain to signal mitophagy prior to mitochondrial outer membrane permeabilization (MOMP) [14]
Summary
Pro-death sensitizer BH3-only proteins bind and inhibit pro-survival Bcl members, while activator BH3-only proteins directly bind and activate Bax and Bak [2], triggering mitochondrial outer membrane permeabilization (MOMP). Recent work has shown that sub-lethal executioner caspase activation is sufficient to stimulate DNA damage and resultant oncogenic transformation [4]. This process has been shown to be triggered by activating MOMP in a subset of mitochondria following sub-lethal doses of apoptotic stimuli [7], suggesting that the MOMP capacity of a cell can determine an apoptotic cell death versus oncogenic transformation decision event
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.