Quantitative assessment of cell fate decision between autophagy and apoptosis

Abstract

Autophagy and apoptosis regulate cell survival and death, and are implicated in the pathogenesis of many diseases. The same type of stress signals can induce either process, but it is unclear how cells ‘assess’ cellular damage and make a ‘life’ or ‘death’ decision by activating autophagy or apoptosis. A computational model of coupled apoptosis and autophagy is built here to study the systems-level dynamics of the underlying signaling network. The model explains the differential dynamics of autophagy and apoptosis in response to various experimental 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 intensity of stress. The model reveals that this dynamic cell fate decision is conferred by a core regulatory network involving cytoplasmic Ca²⁺ 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. The model identified Ca²⁺/calmodulin-dependent kinase kinase β (CaMKKβ) as a determinant of the opposite roles of cytoplasmic Ca²⁺ in autophagy regulation. The results also demonstrated that the model could contribute to the development of pharmacological strategies modulate cell fate decisions.