Birth of a cellular organelle: molecular simulations of lipid droplet budding

  • aula 501 - DIFI
  • Seminar

Speakers

Luca Monticelli
INSERM/CNRS, Lyon, France

Details

Abstract: Lipid droplets (LDs) are organelles regulating lipid storage and metabolism in cells. LD
biogenesis takes place mostly in the endoplasmic reticulum (ER), and starts with the synthesis
of neutral lipids, such as triglycerides. When the concentration of neutral lipids reaches a
certain threshold, oil droplets form by phase-separation, yielding a lens-shaped nascent lipid
droplet – a process known as nucleation. As more neutral lipids are synthesized, the lens
grows and eventually buds out of the ER membrane, generally towards the cytosol, at sites
marked by a specific protein named seipin. Several open questions remain regarding the
mechanism of LD budding, because the initial steps of LD biogenesis are extremely difficult to
observe experimentally. Notably, the roles of ER topology, leaflet asymmetry, and membrane
composition in the budding mechanism are substantially unknown.
Here we present a new, simple methodology allowing to simulate the generation of lipid
droplets in membranes mimicking the topology and composition of the ER, and explore
possible mechanisms of LD budding. Molecular dynamics simulations at the coarse-grained
level are performed out of equilibrium, as in real life experiments. First, we build ER tubular
membranes with realistic size and different compositions, including a realistic ER
composition, then we progressively increase the number of triglyceride molecules in the
system to mimic the effect of triglyceride synthesis and induce budding. We explore different
possibilities for the driving forces of the budding process, including LD volume and ER leaflet
asymmetry, and observe LD budding with different mechanisms depending on the specific
conditions imposed on the system. The simulations allow us to make prediction on the role
of seipin, the localization of phospholipid synthesis, and the stability of the ER-LD connection.
Our methodology pushes the limit of biological simulations allowing, for the first time,
simulations of organelle biogenesis.