Quantitative assessment of cell fate decision between autophagy and apoptosis

Abstract

Autophagy and apoptosis are cellular processes that regulate cell survival and death, the former by eliminating dysfunctional components in the cell, the latter by programmed cell death. Stress signals can induce either process, and it is unclear how cells ‘assess’ cellular damage and make a ‘life’ or ‘death’ decision upon activating autophagy or apoptosis. A computational model of coupled apoptosis and autophagy is built here to analyze the underlying signaling and regulatory network dynamics. The model explains the experimentally observed differential deployment of autophagy and apoptosis in response to various stress signals. Autophagic response dominates at low-to-moderate stress; whereas the response shifts from autophagy (graded activation) to apoptosis (switch-like activation) with increasing stress intensity. The model reveals that cytoplasmic Ca2+ acts as a rheostat that fine-tunes autophagic and apoptotic responses. A G-protein signaling-mediated feedback loop maintains cytoplasmic Ca2+ level, which in turn governs autophagic response through an AMP-activated protein kinase (AMPK)-mediated feedforward loop. Ca2+/calmodulin-dependent kinase kinase β (CaMKKβ) emerges as a determinant of the competing roles of cytoplasmic Ca2+ in autophagy regulation. The study demonstrates that the proposed model can be advantageously used for interrogating cell regulation events and developing pharmacological strategies for modulating cell decisions.

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

“…All these observations point to the utility of a thorough study of the feedback regulation between PKA and ATG proteins in human cells. In this context, dynamical modeling approaches promise to offer helpful pointers [11,[103][104][105][106].…”

“…The targets involved in cardiovascular diseases are mainly calcium channels. Intracellular Ca 2+ can both up-and down-regulate autophagy and plays a key role in the crosstalk between autophagy and apoptosis [11]. The interplay between autophagy and apoptosis renders opposing roles of autophagy as a therapeutic target for cardiovascular diseases.…”

“…calmodulin). Cytoplasmic Ca 2+ inhibits autophagy via activation of calpain and inositol trisphosphate receptor (IP3R), while it also enhances autophagy via activation of AMPK [11]. Our previous study suggested that Ca 2+ /calmodulin-dependent kinase kinase β (CaMKKβ) plays a key role in regulating the balance between these opposing actions and acts as a determinant of the effect of competing roles of cytoplasmic Ca 2+ in autophagy regulation [11].…”

“…Various programmed cell death pathways also exhibit relatively high scores, including apoptosis, necroptosis, and ferroptosis. This is due to a complex crosstalk between autophagy and programmed cell death pathways [71][72][73], which has been shown to process cellular stress signals and confer cell-fate decision [11]. Interestingly, five cell adhesion pathways are top-ranked among cellular processes: regulation of actin cytoskeleton, focal adhesion, gap junction, adherens junction, and tight junction.…”

“…Other important regulators of autophagy include cAMP-dependent protein kinase A (PKA) [10] and other proteins involved in Ca 2+ signaling pathways. Ca 2+ ions have complex effects [11,12]: cytoplasmic Ca 2+ activates Ca 2+ /calmodulin-dependent kinase kinase β (CaMKKβ), which activates AMP-activated protein kinase (AMPK) to promote autophagy [13]. But CaMKKβ also activates calpain, which inhibits autophagy by cleaving autophagy related 5 (Atg5) protein [14].…”