Mitochondrial outer membrane permeabilization and inner membrane permeabilization in regulating apoptosis and inflammation

• Published in: Journal of theoretical biology 2023-08, Vol.571, p.111558-111558, Article 111558
• Main Authors: Qi, Hong, Yin, Yu-Song, Yin, Zhi-Yong, Li, Xiang, Shuai, Jian-Wei
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - physiology; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Dynamic mechanism; Humans; Inflammation; Inflammation - metabolism; Mitochondria - genetics; Mitochondrial inner membrane permeabilization; Mitochondrial Membranes - metabolism; Mitochondrial outer membrane permeabilization
• ISSN: 0022-5193; 1095-8541
• DOI: 10.1016/j.jtbi.2023.111558

•A signaling network linking apoptosis and inflammation by Bcl-2 family proteins is constructed.•The network is converted into an ODE model composed of four modules.•The simulation results are consistent with previous theoretical and experimental results.•The model makes several compelling predictions about cell fate regulation. Recent studies delineate an intimate crosstalk between apoptosis and inflammation. However, the dynamic mechanism linking them by mitochondrial membrane permeabilization remains elusive. Here, we construct a mathematical model consisting of four functional modules. Bifurcation analysis reveals that bistability stems from Bcl-2 family member interaction and time series shows that the time difference between Cyt c and mtDNA release is around 30 min, which are consistent with previous works. The model predicts that Bax aggregation kinetic determines cells to undergo apoptosis or inflammation, and that modulating the inhibitory effect of caspase 3 on IFN-β production allows the concurrent occurrence of apoptosis and inflammation. This work provides a theoretical framework for exploring the mechanism of mitochondrial membrane permeabilization in controlling cell fate.