Biology subjects

Zoni, V.

Publications and source records attributed to Zoni, V..

5 recordsLinked to original sources

bioRxiv2022

Triglyceride lipolysis driven by glucose restriction triggers liquid-crystalline phase transitions and proteome remodeling of lipid droplets

Lipid droplets (LDs) are reservoirs for triglycerides (TGs) and sterol-esters (SEs), but how these lipids are organized within LDs and influence its proteome remains unclear. Using in situ cryoelectron tomography, we show that glucose restriction triggers lipid phase transitions within LDs generating liquid-crystalline lattices inside them. Mechanistically this requires TG lipolysis, which decreases the LD TG:SE ratio, promoting SE transition to a liquid-crystalline phase. Molecular dynamics simulations reveal TG depletion promotes spontaneous TG and SE de-mixing in LDs, additionally altering the lipid packing of the phospholipid monolayer surface. Fluorescence imaging and proteomics further reveal that liquid-crystalline phases are associated with selective remodeling of the LD proteome. Some canonical LD proteins including Erg6 re-localize to the ER network, whereas others remain LD-associated. Model peptide LiveDrop also redistributes from LDs to the ER, suggesting liquid-crystalline-phases influence ER-LD inter organelle transport. Our data suggests glucose restriction drives TG mobilization, which alters the phase properties of LD lipids and selectively remodels the LD proteome.

cell biology↗

bioRxiv2021

Re-charging your fats: Charmm36 parameters for neutral lipids triacylglycerol and diacylglycerol

Neutral lipids (NLs) are an abundant class of cellular lipids. They are characterized by the total lack of charged chemical groups in their structure, and, as a consequence, they play a major role in intracellular lipid storage. NLs that carry a glycerol backbone, such as triacylglycerols (TGs) and diacylglycerols (DGs), are also involved in the biosynthetic pathway of cellular phospholipids, and they have recently been the subject of numerous structural investigations by means of atomistic molecular dynamics (MD) simulations. However, conflicting results on the physicochemical behavior of NLs were observed depending on the nature of the atomistic force field used. Here, we show that current phospholipid-derived CHARMM36 parameters for DGs and TGs cannot reproduce adequately interfacial properties of these NLs, due to excessive hydrophilicity at the glycerol-ester region. By following a CHARMM36-consistent parameterization strategy, we develop new parameters for both TGs and DGs that are compatible with both cutoffbased and Particle Mesh Ewald (PME) schemes for the treatment of Lennard Jones interactions. We show that our new parameters can reproduce interfacial properties of NLs and their behavior in more complex lipid assemblies. We discuss the implications of our findings in the context of intracellular lipid storage and NLs cellular activity.

biophysics↗

bioRxiv2020

Seipin accumulates and traps diacylglycerols and triglycerides in its ring-like structure

Lipid droplets (LD) are intracellular organelles responsible for lipid storage, and they emerge from the endoplasmic reticulum (ER) upon the accumulation of neutral lipids, mostly triglycerides (TG), between the two leaflets of the ER membrane. LD biogenesis takes place at ER sites that are marked by the protein seipin, which subsequently recruits additional proteins to catalyse LD formation. Deletion of seipin, however, does not abolish LD biogenesis, and its precise role in controlling LD assembly remains unclear. Here we use molecular dynamics simulations to investigate the molecular mechanism through which seipin promotes LD formation. We find that seipin clusters TG molecules inside its unconventional ring-like oligomeric structure, and that both its luminal and transmembrane regions contribute to this process. Diacylglycerol, the precursor of TG, also clusters inside the seipin oligomer, in turn promoting TG accumulation. Our results suggest that seipin remodels the membrane of specific ER sites to prime them for LD biogenesis. Significance statementMetabolic disorders related to aberrant fat accumulation, including lipodystrophy and obesity, are a particularly serious health concern. In cells, fat accumulates in intracellular organelles, named lipid droplets (LDs). LDs form in the endoplasmic reticulum, where triglycerides, the most abundant form of fat, is produced. The Bernardinelli-Seip congenital lipodystrophy type 2 protein, seipin, has been identified as a key regulator of LD formation, but its mechanism of action remains debated and its molecular details mostly obscure. Here, we use molecular dynamics simulations to investigate the mechanism of seipin. We find that seipin can cluster and trap both triglycerides and its precursor, diacylglycerol. Our results suggest that seipin organizes the lipid composition of specific ER sites to prime them for LD biogenesis.

cell biology↗

bioRxiv2019

Conserved function of ether lipids and sphingolipids in the early secretory pathway

Sphingolipids have been shown to play important roles in physiology and cell biology, but a systematic examination of their functions is lacking. We performed a genome-wide CRISPRi screen in sphingolipid-depleted cells and identified hypersensitive mutants in genes of membrane trafficking and lipid biosynthesis, including ether lipid synthesis. Systematic lipidomic analysis showed a coordinate regulation of ether lipids with sphingolipids, where depletion of one of these lipid types resulted in increases in the other, suggesting an adaptation and functional compensation. Biophysical experiments on model membranes show common properties of these structurally diverse lipids that also share a known function as GPI anchors in different kingdoms of life. Molecular dynamics simulations show a selective enrichment of ether phosphatidylcholine around p24 proteins, which are receptors for the export of GPI-anchored proteins and have been shown to bind a specific sphingomyelin species. Our results support a model of convergent evolution of proteins and lipids, based on their physico-chemical properties, to regulate GPI-anchored protein transport and maintain homeostasis in the early secretory pathway.

biochemistry↗

bioRxiv2019

Lipid droplet biogenesis is a liquid phase separation spatially regulated by seipin and membrane curvature.

Cells store energy in the form of neutral lipids packaged into micrometer-sized organelles named lipid droplets (LD). These structures emerge from the endoplasmic reticulum (ER), but their biogenesis remains poorly understood. Using molecular simulations, we found that fat accumulation and LD formation are described by a liquid-liquid phase separation (LLPS) process. Within this framework, we could identify how ER membrane properties modulate LD formation, and we could directly test our computational predictions by combining yeast genetics with fluorescence microscopy. Our data suggest that the specific lipid composition of the ER together with its peculiar physical properties, such as low membrane tension and membrane curvature, promote the packaging of neutral lipids into LD, preventing their accumulation in the ER membrane. Our results provide a new conceptual understanding of LD biogenesis in the context of ER homeostasis and function.

cell biology↗