Chain flexibility of medicinal lipids determines their selective partitioning into lipid droplets

Abstract

In guiding lipid droplets (LDs) to serve as storage vessels that insulate high-value lipophilic compounds in cells, we demonstrate that chain flexibility of lipids determines their selective migration in intracellular LDs. Focusing on commercially important medicinal lipids with biogenetic similarity but structural dissimilarity, we computationally and experimentally validate that LD remodeling should be differentiated between overproduction of structurally flexible squalene and that of rigid zeaxanthin and β-carotene. In molecular dynamics simulations, worm-like flexible squalene is readily deformed to move through intertwined chains of triacylglycerols in the LD core, whereas rod-like rigid zeaxanthin is trapped on the LD surface due to a high free energy barrier in diffusion. By designing yeast cells with either much larger LDs or with a greater number of LDs, we observe that intracellular storage of squalene significantly increases with LD volume expansion, but that of zeaxanthin and β-carotene is enhanced through LD surface broadening; as visually evidenced, the outcomes represent internal penetration of squalene and surface localization of zeaxanthin and β-carotene. Our study shows the computational and experimental validation of selective lipid migration into a phase-separated organelle and reveals LD dynamics and functionalization.

Metal cofactor regulation combined with rational genetic engineering of Schizochytrium sp. for high‐yield production of squalene

“…As an intracellular product, the maximal amount of squalene is limited by the available biomass. In addition, the accumulation of lipids is beneficial for squalene production due to their role as a storage compartment for this hydrophobic product (Son et al, 2022). However, lipid production competes with squalene for the common precursor acetyl‐CoA (Liu et al, 2020), resulting in the need for a fine‐tuned balance.…”

“…As an intracellular product, the maximal amount of squalene is limited by the available biomass. In addition, the accumulation of lipids is beneficial for squalene production due to their role as a storage compartment for this hydrophobic product (Son et al, 2022).…”

Solvatochromic Buffering Fluorescent Probe Resolves the Lipid Transport and Morphological Changes during Lipid Droplet Fusion by Super-Resolution Imaging

“…General experimental information, methods, Figures S1−S14, Tables S1 and S2, and 1 H, 13 C, and HRMS spectra for LD-CF (PDF)…”

Compartmentalization engineering of yeasts to overcome precursor limitations and cytotoxicity in terpenoid production

“…Ma et al (2019) observed lycopene accumulated in LDs of S. cerevisiae. The hydrophobic compounds are distributed in different parts of LDs due to their different structures (Son et al, 2022b). Adjusting organelle morphology can be a useful strategy for increasing terpenoid production, which will be introduced in detail below.…”

“…Son et al reported that flexible lipids such as squalene with conjugated π bonds are readily dispersed among TAGs, and squalene production can be enhanced by expanding the volume of the LD. Similarly, rigid lipids such as zeaxanthin and β-carotene are retained between TAGs, and the production of zeaxanthin was enhanced by increasing the LD surface area within the cell (Son et al, 2022b). Thus, LDs are suitable organelles for storing triterpenoids and tetraterpenoids, while strategies that control the size and the number of organelles influence their storage capacity (Figure 4).…”