Formation of autophagosomes coincides with relaxation of membrane curvature

TL;DR

This study uses theoretical modeling to analyze autophagosome formation, revealing that membrane curvature relaxation, rather than vesicle fusion, plays a key role in autophagosome biogenesis.

Contribution

It provides a geometric and energetic framework for understanding autophagosome formation, emphasizing membrane curvature relaxation over vesicle fusion as a driving mechanism.

Findings

Vesicle fusion contributes little to autophagosome formation.

Autophagosome formation involves strong relaxation of membrane curvature energy.

Membrane asymmetries influence the energy landscape of autophagosome precursors.

Abstract

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 modelling 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 preautophagosomal membranes such as vesicles, membrane tubules or sheets. We analyse 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.