Functional analyses and integrated mechanisms of cellular destruction by L-amino acid oxidase
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Snakebite accidents are prevalent worldwide and cause a spectrum of severe clinical manifestations and result in a reduction of patient quality of life and economic income. A major bottleneck in envenomation treatment is our limited understanding of how venom toxins perturb specific cellular processes involved in tissue necrosis. Here, we address this knowledge gap and define the cellular mechanisms via which cell death is triggered by the snake toxin L-amino acid oxidase (LAAO). LAAO is a highly toxic enzyme present in various venoms that causes tissue necrosis, edema, coagulopathies, and organ failure. Here, we identify the residues essential for LAAO oxidation and obtain a catalytically inactive LAAO mutant, which is unable to reproduce the cellular phenotypes. Striking cellular defects are triggered by a catalysis-dependent increase in oxidative stress, via H2O2 (reaction by product). LAAO uptake by cells leads to a decrease in lysosome number and size and inhibits autophagy flux. In parallel, mitochondria function is impaired by severe proton leakage, and mitochondrial fission is stimulated, causing their engulfment by autophagosomes. However, mitochondrial clearance is prevented by the lysosomal defects. The concurrent shutdown of cell respiration and energy consumption indicates that LAAO catalysis reduces both metabolism and cell fitness. Thus, essential organelles are coordinately impaired by LAAO activity, accelerating cell demise. Considering the multi-organelle impairment, strategies to reduce organelle injury after LAAO exposure may be effective to maintain critical cell functions and strengthen adaptive responses against cytotoxicity.
Date Issued
2026-01-16
Date Acceptance
2025-10-22
Citation
Cell Death and Disease, 2026, 17
ISSN
2041-4889
Publisher
Nature Publishing Group
Journal / Book Title
Cell Death and Disease
Volume
17
Copyright Statement
© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
10.1038/s41419-025-08187-7
Subjects
autophagy
cytotoxicity
mitochondrial stress
organelle failure
Publication Status
Published
Coverage Spatial
Great Britain
Article Number
ARTN 48
Date Publish Online
2025-11-20