COMPUTER SIMULATIONS UNVEIL THE DYNAMICS OF AUTOPHAGY AND ITS IMPLICATIONS FOR THE CELLULAR QUALITY CONTROL

Abstract

Since the discovery of autophagy half a century ago, a number of physiological and molecular-level studies of autophagy have been carried out, revealing the basic mechanism and role of autophagy in the protein and organelle quality control. However, a reliable assessment method for the autophagy-mediated protein/organelle quality control with the help of an adequate mathematical model has not yet been reported. Based on the previous mathematical modeling of autophagy, we have carried out simulations to prove whether and how basal autophagy achieves substrate specificity and contributes to the cellular protein/organelle quality control. By means of numerical simulations, we probe the selective autophagic mode and observe that autophagic fluxes from abnormal protein/organelle are much greater than those from resident protein/organelle. Such a selective autophagic mode is found to correlate with the fractional abnormal protein/organelle concentration. Finally, it is shown that the fractional abnormal protein/organelle concentration against cellular damaging is efficiently controlled and regulated by suppression or promotion of the autophagosome formation rate. Mathematical modeling and numerical simulations allow one to analyze the autophagic protein/organelle quality control in a specific and quantitative manner and disclose that autophagy serves as a critical cellular quality control mechanism.