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.

Alterations of mitochondrial dynamics allow retrograde propagation of locally initiated axonal insults

“…While spreading of degenerative signal may be caused by damaged mitochondria moving to unchallenged, our results showing that rotenone induces a dramatic slowdown of mitochondrial movement and speed are not in favor of that scenario. Interestingly, theoretical studies have shown that spreading of apoptosis signals may occur through diffusion of locally-activated executive apoptotic proteins 69 70 . Although not addressing directly these specific questions, our data suggest that mitochondrial integrity is crucial in the axonal diffusion of executive apoptotic factors, as fissionned mitochondria lose their capacity to prevent retrograde propagation of apoptotic factors in axons in the case of intercurrent stress.…”

Evaluating biomarkers to model cancer risk post cosmic ray exposure

“…Fewer models have linked ROS production in mitochondria to other cellular processes ( Jafri and Kumar, 2014 ). The role of ROS in apoptosis has been included in models regulating mitochondrial membrane permeabilization ( Jacob et al, 2016 ) and in transition pore opening ( Bagci et al, 2006 ). ROS functioning as a determinant of cell fate has also been incorporated in a multistage model of tumorigenesis, however, the robustness of this model has not been validated with experimental evidence based on predictions ( Chaudhary et al, 2011 ).…”

Cathepsin B mediates the lysosomal-mitochondrial apoptosis pathway in arsenic-induced microglial cell injury

“…20 After cleavage by cathepsin B, Bcl-2 members are transferred to mitochondria to activate and bind Bax/Bak1, 21 causing mitochondrial membrane permeabilization (MMP), which induces the mitochondrial apoptotic pathway. 22 Notably, the cathepsin B-mediated lysosome-mitochondrial apoptosis pathway plays a crucial role in various diseases, 23 and Wang et al 15 have discovered that the destruction of lysosomes and mitochondria could cause the death of cells exposed to arsenic. However, lysosome-mitochondrial-mediated microglial apoptosis is unclear in arsenic-induced microglial injury.…”