Vesicle cholesterol controls exocytotic fusion pore

Rituper, Boštjan (author), Guček, Alenka (author), Lisjak, Marjeta (author), Górska, Urszula (author), Trkov, Saša (author), Lasič, Eva (author), Božić, Mićo (author), Jorgačevski, Jernej (author), Kreft, Marko (author), Stenovec, Matjaž (author), Božič, Bojan (author), Zorec, Robert (author)

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 Ca$^{2+}$-dependent exocytosis regulated by distinct Ca$^{2+}$ sources, evokes vesicle secretion. Although this treatment enhanced cytosolic levels of Ca$^{2+}$ 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.

• Language: English
• Keywords: cholesterol, exocytosis, fusion pore conductance, constriction force, fusion pore widening and constriction, lysosomal storage disease
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2022
• Number of pages: 17 str.
• Numbering: Vol. 101, art. 102503
• PID: 20.500.12556/RUL-138888
• UDC: 616-092
• ISSN on article: 1532-1991
• DOI: 10.1016/j.ceca.2021.102503
• COBISS.SI-ID: 87034627
• Publication date in RUL: 24.08.2022

Record is a part of a journal

• Title: Cell calcium
• Shortened title: Cell calcium
• Publisher: Elsevier
• ISSN: 1532-1991
• COBISS.SI-ID: 77488387

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: holesterol, eksocitoza, prevodnost fuzijskih por