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Sterol Metabolism Differentially Contributes to Maintenance and Exit of Quiescence
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.ORCID iD: 0000-0002-2924-7045
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.ORCID iD: 0000-0002-6955-3901
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.ORCID iD: 0000-0002-2782-6203
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Number of Authors: 92022 (English)In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 10, article id 788472Article in journal (Refereed) Published
Abstract [en]

Nutrient starvation initiates cell cycle exit and entry into quiescence, a reversible, non-proliferative state characterized by stress tolerance, longevity and large-scale remodeling of subcellular structures. Depending on the nature of the depleted nutrient, yeast cells are assumed to enter heterogeneous quiescent states with unique but mostly unexplored characteristics. Here, we show that storage and consumption of neutral lipids in lipid droplets (LDs) differentially impacts the regulation of quiescence driven by glucose or phosphate starvation. Upon prolonged glucose exhaustion, LDs were degraded in the vacuole via Atg1-dependent lipophagy. In contrast, yeast cells entering quiescence due to phosphate exhaustion massively over-accumulated LDs that clustered at the vacuolar surface but were not engulfed via lipophagy. Excessive LD biogenesis required contact formation between the endoplasmic reticulum and the vacuole at nucleus-vacuole junctions and was accompanied by a shift of the cellular lipid profile from membrane towards storage lipids, driven by a transcriptional upregulation of enzymes generating neutral lipids, in particular sterol esters. Importantly, sterol ester biogenesis was critical for long-term survival of phosphate-exhausted cells and supported rapid quiescence exit upon nutrient replenishment, but was dispensable for survival and regrowth of glucose-exhausted cells. Instead, these cells relied on de novo synthesis of sterols and fatty acids for quiescence exit and regrowth. Phosphate-exhausted cells efficiently mobilized storage lipids to support several rounds of cell division even in presence of inhibitors of fatty acid and sterol biosynthesis. In sum, our results show that neutral lipid biosynthesis and mobilization to support quiescence maintenance and exit is tailored to the respective nutrient scarcity.

Place, publisher, year, edition, pages
2022. Vol. 10, article id 788472
Keywords [en]
lipid droplets, membrane contact sites, NVJ, yeast, quiescence, lipophagy, sterol ester, sterols
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-203129DOI: 10.3389/fcell.2022.788472ISI: 000761993600001PubMedID: 35237594Scopus ID: 2-s2.0-85125340822OAI: oai:DiVA.org:su-203129DiVA, id: diva2:1646722
Available from: 2022-03-23 Created: 2022-03-23 Last updated: 2026-01-26Bibliographically approved
In thesis
1. Spatial organization of lipid droplet catabolism in yeast
Open this publication in new window or tab >>Spatial organization of lipid droplet catabolism in yeast
2025 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Eukaryotic cells store lipids in specialized organelles termed lipid droplets (LDs), composed of a core of neutral lipids surrounded by a phospholipid monolayer. The biosynthesis and consumption of LDs is under the control of the nutritional state of the cell, and  conserved molecular pathways allow cells to sense and respond to fluctuating nutrient availability, facilitating metabolic adaptation and subcellular reorganization. This thesis explores distinct alterations in lipid metabolism as cells age, adapt to nutrient scarcity and are challenged with fresh nutrients to re-enter the cell cycle, using the budding yeast Saccharomyces cerevisiae as unicellular eukaryotic model organism. A special emphasis is placed on the dynamic balance between LD formation and catabolism, in particular the two main cellular routes to consume LDs, namely lipolysis and lipophagy. In Paper I, we unravel how the exhaustion of either glucose or phosphate affects LD biosynthesis and consumption, showing that these processes differently contribute to the maintenance and exit of quiescence depending on the respective nutrient limitation. In Paper II, we identify the tethering machinery that enables LDs to dock to the vacuolar membrane during lipophagy for subsequent microautophagic degradation of LDs within the vacuolar lumen. We demonstrate that this novel organelle contact site, termed vCLIP for vacuole-lipid droplet contact site, is critical for efficient lipophagy and long-term survival during glucose restriction. In Paper III, we show that cytosolic lipases assemble into distinct foci on the LD surface to drive lipolysis in response to starvation. Finally, in paper IV, we demonstrate that the lipolysis machinery, so far only connected to the cytosolic turnover of LDs, is essential for LD consumption in the vacuole during lipophagy. Collectively, our results provide mechanistic insights into distinct aspects of LD catabolism during nutritional stress and introduce a concept of LD consumption where the coordinated activity of lipophagy and lipolysis allows cells to adapt to changing metabolic demands.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, 2025. p. 60
Keywords
Lipid droplets, catabolism, lipophagy, lipolysis, vacuolar lipolysis, lipase, contact sites, vCLIP, stationary phase
National Category
Biological Sciences
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-245356 (URN)978-91-8107-344-7 (ISBN)978-91-8107-345-4 (ISBN)
Public defence
2025-09-11, Vivi Täckholmssalen (Q211), NPQ-huset, Svante Arrhenius väg 20 and online via Zoom: https://stockholmuniversity.zoom.us/j/63108066782, Stockholm, 10:00 (English)
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Supervisors
Available from: 2025-08-19 Created: 2025-08-06 Last updated: 2025-08-14Bibliographically approved
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Peselj, CarlottaEbrahimi, MahsaBroeskamp, FilomenaProkisch, SimonHabernig, LukasAlvarez-Guerra, IreneKohler, VerenaBüttner, Sabrina

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Peselj, CarlottaEbrahimi, MahsaBroeskamp, FilomenaProkisch, SimonHabernig, LukasAlvarez-Guerra, IreneKohler, VerenaBüttner, Sabrina
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