Basal State Calibration of a Chemical Reaction Network Model for Autophagy.

The modulation of autophagy plays a dual role in tumor cells, with the potential to both promote and suppress tumor proliferation. In order to gain a deeper understanding of the nature of autophagy, we have developed a chemical reaction kinetic model of autophagy and apoptosis based on the mass action kinetic models that have been previously described in the literature. It is regrettable that the authors did not provide all of the information necessary to reconstruct their model, which made their simulation results irreproducible.

Oscillation of Autophagy Induction under Cellular Stress and What Lies behind It, a Systems Biology Study.

One of the main inducers of autophagy-dependent self-cannibalism, called ULK1, is tightly regulated by the two sensor molecules of nutrient conditions and energy status, known as mTOR and AMPK kinases, respectively. Recently, we developed a freely available mathematical model to explore the oscillatory characteristic of the AMPK-mTOR-ULK1 regulatory triangle. Here, we introduce a systems biology analysis to explain in detail the dynamical features of the essential negative and double-negative feedback loops and also the periodic repeat of autophagy induction upon cellular stress.

Fine-Tuning of mTORC1-ULK1-PP2A Regulatory Triangle Is Crucial for Robust Autophagic Response upon Cellular Stress.

Autophagy-dependent cellular survival is tightly regulated by both kinases and phosphatases. While mTORC1 inhibits autophagy by phosphorylating ULK1, PP2A is able to remove this phosphate group from ULK1 and promotes the key inducer of autophagosome formation. However, ULK1 inhibits mTORC1, mTORC1 is able to down-regulate PP2A.

Fine-tuning of AMPK-ULK1-mTORC1 regulatory triangle is crucial for autophagy oscillation.

Autophagy is an intracellular digestive process, which has a crucial role in maintaining cellular homeostasis by self-eating the unnecessary and/or damaged components of the cell at various stress events. ULK1, one of the key elements of autophagy activator complex, together with the two sensors of nutrient and energy conditions, called mTORC1 and AMPK kinases, guarantee the precise function of cell response mechanism. We claim that the feedback loops of AMPK-mTORC1-ULK1 regulatory triangle determine an accurate dynamical characteristic of autophagic process upon cellular stress.

A Double Negative Feedback Loop between mTORC1 and AMPK Kinases Guarantees Precise Autophagy Induction upon Cellular Stress.

Cellular homeostasis is controlled by an evolutionary conserved cellular digestive process called autophagy. This mechanism is tightly regulated by the two sensor elements called mTORC1 and AMPK. mTORC1 is one of the master regulators of proteostasis, while AMPK maintains cellular energy homeostasis.