Autophagy is an intracellular degradation process that employs complex membrane dynamics to isolate and break down cellular components. However, many unanswered questions remain concerning remodeling of autophagic membranes. Here, we focus on the advantages of theoretical modeling to study the formation of autophagosomes and to understand the origin of autophagosomal membranes. Starting from the well-defined geometry of final autophagosomes, we ask the question of how these organelles can be formed by combining various pre-autophagosomal membranes such as vesicles, membrane tubules, or sheets. We analyze the geometric constraints of autophagosome formation by taking the area of the precursor membranes and their internal volume into account. Our results suggest that vesicle fusion contributes little to the formation of autophagosomes. In the second part, we quantify the curvature of the precursors and report that the formation of autophagosomes is associated with a strong relaxation of membrane curvature energy. This effect we find for a wide range of membrane asymmetries. It is especially strong for small distances between both autophagosomal membranes, as observed in vivo. We quantify the membrane bending energies of all precursors by considering membrane asymmetries. We propose that the generation and supply of pre-autophagosomal membranes is one limiting step for autophagosome formation.
Keywords: Bending energy; Fusion; Membrane curvature; Membrane remodeling; Retrograde autophagy; Reverse autophagy; Scission; Theory modeling.