Boštjan Rituper (Author), Alenka Guček (Author), Marjeta Lisjak (Author), Urszula Górska (Author), Aleksandra Šakanović (Author), Saša Trkov (Author), Eva Lasič (Author), Mićo Božić (Author), Jernej Jorgačevski (Author), Marko Kreft (Author), Alexei Verkhratsky (Author), Gregor Anderluh (Author), Matjaž Stenovec (Author), Bojan Božič (Author), Robert Zorec (Author)

Abstract

In some lysosomal storage diseases (LSD) cholesterol accumulates in vesicles. Whether increased vesicle cholesterol affects vesicle fusion with the plasmalemma, where the fusion pore, a channel between the vesicle lumen and the extracellular space, is formed, is unknown. Super-resolution microscopy revealed that after stimulation of exocytosis, pituitary lactotroph vesicles discharge cholesterol which transfers to the plasmalemma. Cholesterol depletion in lactotrophs and astrocytes, both exhibiting Ca2+-dependent exocytosis regulated by distinct Ca2+sources, evokes vesicle secretion. Although this treatment enhanced cytosolic levels of Ca2+ in lactotrophs but decreased it in astrocytes, this indicates that cholesterol may well directly define the fusion pore. In an attempt to explain this mechanism, a new model of cholesterol-dependent fusion pore regulation is proposed. High-resolution membrane capacitance measurements, used to monitor fusion pore conductance, a parameter related to fusion pore diameter, confirm that at resting conditions reducing cholesterol increases, while enrichment with cholesterol decreases the conductance of the fusion pore. In resting fibroblasts, lacking the Npc1 protein, a cellular model of LSD in which cholesterol accumulates in vesicles, the fusion pore conductance is smaller than in controls, showing that vesicle cholesterol controls fusion pore and is relevant for pathophysiology of LSD.

Keywords

cholesterol;exocytosis;fusion pore conductance;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL MF - Faculty of Medicine
UDC: 616-092
COBISS: 87034627 Link will open in a new window
ISSN: 1532-1991
Views: 189
Downloads: 59
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Other data

Secondary language: Slovenian
Secondary keywords: holesterol;eksocitoza;prevodnost fuzijskih por;
Type (COBISS): Article
Pages: str. 1-17
Issue: ǂVol. ǂ101
Chronology: 2022
DOI: 10.1016/j.ceca.2021.102503
ID: 16261721