Spotlight on “Proximity proteomics reveals a mechanism of fatty acid transfer at lipid droplet-mitochondria- endoplasmic reticulum contact sites” by Bezawork-Geleta et al. 2025

The research conducted by Ayenachew Bezaworj-Gelata and colleagues, published in Nature Communications in 2025, uncovered a fascinating mechanism for fatty acid transfer at lipid droplet-mitochondria-endoplasmic reticulum contact sites.Via use of biotinylation-dependent proximity proteomics Bezaworj-Gelata et al. identified a total of 71 proteins at lipid dropletmitochondria contact sites, including a multimeric complex containing extended synaptotagmin (ESYT) 1, ESYT2, and VAMP Associated Protein B and C (VAPB).Intriguingly, mutagenesis of ESYT1, ESYT2 or VAPB limits lipid droplet-derived fatty acid oxidation, resulting in depletion of tricarboxylic acid cycle metabolites, remodelling of the cellular lipidome, and induction of lipotoxic stress in cell culture.These phenotypes were additionally observed in Esyt1 and Esyt2 deficient mice.These results uncover a fundamental mechanism that is required for lipid droplet-derived fatty acid oxidation and cellular lipid homoeostasis, with consequences for metabolic diseases and survival, yet even broader implications regarding the cross-Kingdom integration of organellar metabolisms.