Autophagy and apoptosis are regulated by stress on Bcl2 by AMBRA1 in the endoplasmic reticulum and mitochondria.

BACKGROUND: Autophagy and apoptosis are two important physiological processes that determine cell survival or death in response to different stress signals. The regulatory mechanisms of these two processes share B-cell lymphoma-2 family proteins and AMBRA1, which are present in both the endoplasmic reticulum and mitochondria. B-cell lymphoma-2 family proteins sense different stresses and interact with AMBRA1 to regulate autophagy and apoptosis, which are respectively mediated by Beclin1 and Caspases. Therefore, we investigated how different levels of stress on B-cell lymphoma-2 family proteins that bind to AMBRA1 in the endoplasmic reticulum and mitochondria regulate the switch from autophagy to apoptosis. METHODS: In this paper, we considered the responses of B-cell lymphoma-2 family proteins, which bind to AMBRA1 in both the endoplasmic reticulum and mitochondria, to two different levels of stress in a model originally proposed by Kapuy et al. We investigated how these two stress levels affect the transition from autophagy to apoptosis and their effects on apoptosis activation over time. Additionally, we analyzed how the feedback regulation in this model affects the bifurcation diagrams of two levels of stress and cell fate decisions between autophagy and apoptosis. RESULTS: Autophagy is activated for minor stress in mitochondria regardless of endoplasmic reticulum stress, while apoptosis is activated for only significant stress in mitochondria. Apoptosis is only sensitive to mitochondria stress. The time duration before apoptosis activation is longer in the presence of high AMBRA1 levels with high endoplasmic reticulum and mitochondria stress. AMBRA1 can compete with B-cell lymphoma-2 family proteins to bind and activate Beclin1 and thus promote the autophagy process for a long time before apoptosis. Furthermore, apoptosis is prone to occur with increasing activation of Caspases, inactivation of Beclin1-A and the Michaelis constant of Caspases. CONCLUSION: A novel mathematical model has been developed to understand the complex regulatory mechanisms of autophagy and apoptosis. Our model may be applied to further autophagy-apoptosis dynamic modeling experiments and simulations.

Bifurcation analysis and potential landscapes of the p53-Mdm2 module regulated by the co-activator programmed cell death 5.

The dynamics of p53 play important roles in the regulation of cell fate decisions in response to various stresses, and programmed cell death 5 (PDCD5) functions as a co-activator of p53 that modulates p53 dynamics. In the present paper, we investigated how p53 dynamics are modulated by PDCD5 during the deoxyribose nucleic acid damage response using methods of bifurcation analysis and potential landscape. Our results revealed that p53 activities display rich dynamics under different PDCD5 levels, including monostability, bistability with two stable steady states, oscillations, and the coexistence of a stable steady state (or two states) and an oscillatory state. The physical properties of the p53 oscillations were further demonstrated by the potential landscape in which the potential force attracts the system state to the limit cycle attractor, and the curl flux force drives coherent oscillation along the cyclic trajectory. We also investigated the efficiency with which PDCD5 induced p53 oscillations. We show that Hopf bifurcation can be induced by increasing the PDCD5 efficiency and that the system dynamics exhibited clear transition features in both barrier height and energy dissipation when the efficiency was close to the bifurcation point.

Bifurcation analyses and potential landscapes of a cortex-basal ganglia-thalamus model.

The dynamics of cortical neuronal activity plays important roles in controlling body movement and is regulated by connection weights between neurons in a cortex-basal ganglia-thalamus (BGCT) loop. Beta-band oscillation of cortical activity is closely associated with the movement disorder of Parkinson's disease, which is caused by an imbalance in the connection weights of direct and indirect pathways in the BGCT loop. In this study, the authors investigate how the dynamics of cortical activity are modulated by connection weights of direct and indirect pathways in the BGCT loop under low dopamine levels through bifurcation analyses and potential landscapes. The results reveal that cortical activity displays rich dynamics under different connection weights, including one, two, or three stable steady states, one or two stable limit cycles, and the coexistence of one stable limit cycle with one stable steady state or two stable ones. For a low dopamine level, cortical activity exhibits oscillation for larger connection weights of direct and indirect pathways. The stability of these stable dynamics is explored by the potential landscapes.

Stochasticity and bifurcations in a reduced model with interlinked positive and negative feedback loops of CREB1 and CREB2 stimulated by 5-HT.

The cyclic AMP (cAMP)-response element-binding protein (CREB) family of transcription factors is crucial in regulating gene expression required for long-term memory (LTM) formation. Upon exposure of sensory neurons to the neurotransmitter serotonin (5-HT), CREB1 is activated via activation of the protein kinase A (PKA) intracellular signaling pathways, and CREB2 as a transcriptional repressor is relieved possibly via phosphorylation of CREB2 by mitogen-activated protein kinase (MAPK). Song et al. [18] proposed a minimal model with only interlinked positive and negative feedback loops of transcriptional regulation by the activator CREB1 and the repressor CREB2. Without considering feedbacks between the CREB proteins, Pettigrew et al. [8] developed a computational model characterizing complex dynamics of biochemical pathways downstream of 5-HT receptors. In this work, to describe more simply the biochemical pathways and gene regulation underlying 5-HT-induced LTM, we add the important extracellular sensitizing stimulus 5-HT as well as the product Ap-uch into the Song's minimal model. We also strive to examine dynamical properties of the gene regulatory network under the changing concentration of the stimulus, [5-HT], cooperating with the varying positive feedback strength in inducing a high state of CREB1 for the establishment of long-term memory. Different dynamics including monostability, bistability and multistability due to coexistence of stable steady states and oscillations is investigated by means of codimension-2 bifurcation analysis. At the different positive feedback strengths, comparative analysis of deterministic and stochastic dynamics reveals that codimension-1 bifurcation with respect to [5-HT] as the parameter can predict diverse stochastic behaviors resulted from the finite number of molecules, and the number of CREB1 molecules more and more preferentially resides near the high steady state with increasing [5-HT], which contributes to long-term memory formation.