Affordable Access

Access to the full text

Emerging mechanisms of drug-induced phospholipidosis

Authors
  • Breiden, Bernadette1
  • Sandhoff, Konrad1
  • 1 Membrane Biology and Lipid Biochemistry Unit, c/o Kekulé-Institut für Organische Chemie und Biochemie, Universität Bonn, Gerhard-Domagk-Str. 1 , (Germany)
Type
Published Article
Journal
Biological Chemistry
Publisher
Walter de Gruyter GmbH
Publication Date
Aug 13, 2019
Volume
401
Issue
1
Pages
31–46
Identifiers
DOI: 10.1515/hsz-2019-0270
Source
De Gruyter
Keywords
License
Yellow

Abstract

Drug-induced phospholipidosis is a lysosomal storage disorder characterized by excessive accumulation of phospholipids. Its cellular mechanism is still not well understood, but it is known that cationic amphiphilic drugs can induce it. These drugs have a hydrophilic amine head group that can be protonated in the endolysosomal compartment. As cationic amphiphiles, they are trapped in lysosomes, where they interfere with negatively charged intralysosomal vesicles, the major platforms of cellular sphingolipid degradation. Metabolic principles observed in sphingolipid and phospholipid catabolism and inherited sphingolipidoses are of great importance for lysosomal function and physiological lipid turnover at large. Therefore, we also propose intralysosomal vesicles as major platforms for degradation of lipids and phospholipids reaching them by intracellular pathways like autophagy and endocytosis. Phospholipids are catabolized as components of vesicle surfaces by protonated, positively charged phospholipases, electrostatically attracted to the negatively charged vesicles. Model experiments suggest that progressively accumulating cationic amphiphilic drugs inserting into the vesicle membrane with their hydrophobic molecular moieties disturb and attenuate the main mechanism of lipid degradation as discussed here. By compensating the negative surface charge, cationic enzymes are released from the surface of vesicles and proteolytically degraded, triggering a progressive lipid storage and the formation of inactive lamellar bodies.

Report this publication

Statistics

Seen <100 times