Abstracts
Cathepsin-dependent amyloid formation drives mechanical rupture of lysosomal membranes
Presenting author: Wenxin Zhang
Max Planck Institute of Biophysics, Mechanisms of Cellular Quality Control, Max-von-Laue-Straße 3, 60438 Frankfurt am Main [DE], wenxin.zhang@biophys.mpg.de
Author(s):
Wenxin Zhang, Delong Li, Florian Wilfling
Lysosomal membrane integrity is essential for cellular homeostasis, and its failure drives lysosomal storage disorders (LSD) and neurodegeneration. The dipeptide L-leucyl-L-leucine methyl ester (LLOMe) is widely used to model lysosomal damage, yet its mechanism remains poorly understood. The prevailing view holds that LLOMe polymerizes into membrane-permeabilizing peptide chains within the lysosomal lumen. Using cryo-electron tomography in cultured cells and primary neurons, we visualized the structural basis of LLOMe-induced lysosomal damage. We reveal that LLOMe forms amyloid structures within lysosomes that directly interact with and rupture the limiting membrane through mechanical stress. In vitro reconstitution confirms this amyloid-mediated mechanism. These findings establish a structural paradigm for lysosomal membrane disruption and provide insights into how disease-relevant protein aggregates, implicated in neurodegeneration and LSD, may compromise lysosomal integrity.