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FRIMEDBIO-Fri prosj.st. med.,helse,biol

The composition and function of lipid droplet contact sites

Alternative title: Hvordan snakker cellulære «lipid droplets» med andre celleorganeller?

Awarded: NOK 3.9 mill.

Project Manager:

Project Number:

301369

Project Period:

2020 - 2024

Partner countries:

Cellular membranes are crucial for all living cells. Every cell is enveloped by a lipid membrane, and all eukaryotic cells contain membrane-bound organelles. Cellular membranes are composed of a lipid bilayer and various membrane-associated proteins. To maintain cellular homeostasis, organelles need to communicate with each other through membrane contact sites. These membrane contact sites are formed when specific proteins and phospholipids hold membranes from different organelles in very close proximity, without any fission or fusion. Virtually all cellular organelles are known to communicate via membrane contact sites to exchange molecules, such as lipids or ions. The ER is the largest membrane-bound organelle in the cell and reaches throughout the whole cell. It plays a central role in the synthesis of new lipids, and establishes membrane contact sites with numerous other organelles. One function of these membrane contact sites is to transport newly synthesized lipids to other organelles, such as mitochondria or lipid droplets. This lipid transfer at membrane contact sites can also be used to generate new cellular membranes or extend an existing membrane structure. The ER and its contact sites play a major role in the cellular process of autophagy, which is important for degrading damaged organelles and maintaining nutrient flux under nutrient-poor conditions. Autophagy encloses cytosolic cargo or damaged organelles into a membrane-bound organelle called an autophagosome. The contents of the autophagosome are then degraded, which returns nutrients to the cell. A critical step in autophagy is the generation of the enclosing membrane, called the phagophore, at specialized regions of the ER. At these regions, membrane material from various sources in the cell is assembled into a phagophore which is held in very close proximity to the ER. To extend the membrane of the phagophore, a membrane contact site is created between the ER and the growing phagophore to allow direct transfer of lipids. The phagophore grows and engulfs the cargo to form a closed vesicle, the autophagosome, which can then fuse with lysosomes to degrade the cargo. The lipid-binding protein DFCP1 localizes to these ER-phagophore membrane contact sites. It is widely used as an early autophagy marker, however its function at these ER regions was entirely unknown. In this collaborative work between the Stenmark and Ikonen groups, a new protein domain of DFCP1 has been identified and characterized. This protein domain, an ATPase, is responsible for breaking down ATP (Adenosine Triphosphate) molecules into ADP (Adenosine Diphosphate) and inorganic phosphate. We found that DFCP1 can bind and break down ATP, which is crucial for the closure of omegasomes after they have been filled with specific cargo, such as mitochondria, protein aggregates, and micronuclei. Furthermore, we identified DFCP1 mutants that are unable to bind and break down ATP. As a result, these omegasomes cannot constrict properly, causing a delay in the release of nascent autophagosomes. Overall, this research provides important insights into the role of DFCP1 in the process of selective autophagy and sheds light on the mechanisms of omegasome closure.

Every living cell is enveloped by a membrane, which is composed of proteins and lipids. Lipids are providing energy for the cell and are used as basic building blocks for signaling molecules. Cells can store lipids in specific organelles, called lipid droplets (LDs). In order to fulfill their various cellular functions, lipid droplets communicate with other organelles, such as ER, mitochondria or peroxisomes. If membranes of two organelles are in close apposition, membrane contact sites can be established, which allow the exchange of lipids, ions and other small molecules. However, the molecular mechanisms underlying such membrane contacts sites are poorly understood. In the work presented, I aim to understand the molecular composition and the function of lipid droplet membrane contact sites. More specifically, I aim to identify unknown proteins which constitute lipid droplet contact sites. Using advanced microscopy I will visualize these membrane contact sites in living cells. Next, I will perturb the establishment of lipid droplet contact sites and test how they affect the communication with other organelles. Finally, I will test if contact site proteins are deregulated in cancer cells, and assess cell proliferation upon depletion of these contact sites. This project will give us a deeper understanding of how cell organelles communicate with each other to transfer lipids. The knowledge gained in cellular lipid metabolism provides a basis to develop therapies against diseases which involve lipid droplets, such as diabetes, obesity, cardiovascular diseases and cancer.

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Funding scheme:

FRIMEDBIO-Fri prosj.st. med.,helse,biol

Funding Sources