Introduction Macroautophagy (hereafter referred to as autophagy) is a key homeostatic mechanism for the turnover of such intracellular components as proteins/organelles, and is further related to various physiopathological conditions of the eukaryotic cell. The aim of this study is to propose a new integrative approach to the quantitative analysis of the autophagy pathway. Methods We develop a 'minimal autophagy model' which assumes a three-compartment description of the process, i.e., autophagosome, autolysosome, and protein/organelle compartments. The interactions among these compartments and the rates at which the concentrations of autophagosomes, autolysosomes, and protein/organelles vary with time are expressed mathematically. In the model, we describe the autophagosome/autolysosome formation specific rates as functions of the intracellular concentrations of ATP andamino acids. Furthermore, the distinct dynamical characteristics between the autophagosome/autolysosome from resident protein/organelle and those from abnormal protein/organelle are considered. Then two quantitative indices measuring autophagy activities in the induction of sequestration fluxes and in the selective degradation are definedon the basis of the model. Results and Discussion Via computer simulations, we reconstruct key profiles of the autophagic process such as the time evolution of autophagy fluxes, levels of autophagosomes/autolysosomes, and corresponding cellular changes at good time resolution, from the biological experiments of the target autophagy system. Then, the target autophagy system is interpreted with the help of the quantitative autophagy not only to examine how the autophagy system responds to cellular damaging but also to prove the causal relationships among the steady-state autophagy levels, autophagic fluxes, and corresponding cellular changes in a specific and quantitative manner. Conclusions To develop such integrative approaches to the quantitative analysis of the autophagy pathway, based on the mathematical modeling and the simulation-based analysis, is highly challenging but indispensable for the assessment of the autophagy activity and of its roles associated with different physiopathological states of human diseases.

Computer-aided analysis of autophagy pathway

254th National Meeting (2017)

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