title: An Analysis of the Truncated Bid- and ROS-dependent Spatial Propagation of Mitochondrial Permeabilization Waves during Apoptosis.
abstract: Apoptosis is a form of programmed cell death that is essential for the efficient elimination of surplus, damaged, and transformed cells during metazoan embryonic development and adult tissue homeostasis. Situated at the interface of apoptosis initiation and execution, mitochondrial outer membrane permeabilization (MOMP) represents one of the most fundamental processes during apoptosis signal transduction. It was shown that MOMP can spatiotemporally propagate through cells, in particular in response to extrinsic apoptosis induction. Based on apparently contradictory experimental evidence, two distinct molecular mechanisms have been proposed to underlie the propagation of MOMP signals, namely a reaction-diffusion mechanism governed by anisotropies in the production of the MOMP-inducer truncated Bid (tBid), or a process that drives the spatial propagation of MOMP by sequential bursts of reactive oxygen species. We therefore generated mathematical models for both scenarios and performed in silico simulations of spatiotemporal MOMP signaling to identify which one of the two mechanisms is capable of qualitatively and quantitatively reproducing the existing data. We found that the explanatory power of each model was limited in that only a subset of experimental findings could be replicated. However, the integration of both models into a combined mathematical description of spatiotemporal tBid and reactive oxygen species signaling accurately reproduced all available experimental data and furthermore, provided robustness to spatial MOMP propagation when mitochondria are spatially separated. Our study therefore provides a theoretical framework that is sufficient to describe and mechanistically explain the spatiotemporal propagation of one of the most fundamental processes during apoptotic cell death.
authors.affiliation: From the Department of Physiology & Medical Physics and Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Selma F
authors.initials: SF
authors.lastname: Jacob
authors.affiliation: From the Department of Physiology & Medical Physics and Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Maximilian L
authors.initials: ML
authors.lastname: Würstle
authors.affiliation: From the Department of Physiology & Medical Physics and Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: M Eugenia
authors.initials: ME
authors.lastname: Delgado
authors.affiliation: From the Department of Physiology & Medical Physics and Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland mrehm@rcsi.ie.
authors.forename: Markus
authors.initials: M
authors.lastname: Rehm
mesh_terms: D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000737:chemistry / Q000378:metabolism*; D002463:Cell Membrane Permeability; D048429:Cell Size; D019295:Computational Biology; D003198:Computer Simulation; D004058:Diffusion; D047108:Embryonic Development; D005103:Expert Systems; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D063154:Mitochondrial Dynamics; D051336:Mitochondrial Membranes / Q000378:metabolism*; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D010446:Peptide Fragments; D017382:Reactive Oxygen Species
keywords: B-cell lymphoma 2 (Bcl-2) family; apoptosis; mathematical modeling; mitochondrial outer membrane permeabilization; reactive oxygen species (ROS); spatiotemporal signalling; systems biology