Molecular basis of organelle tethering during adipocyte differentiation

Contact sites between organelles are vital to the function of eukaryotic cells. Lipid droplets are dynamic organelles specialized in lipid storage, and interact physically with mitochondria in several cell types. The mechanisms generating this contact site are, however, poorly understood. Here, we discover in adipocytes, professional fat storing cells, that the mitochondrial outer-membrane protein MIGA2 tethers mitochondria to lipid droplets. We identify a lipid droplet targeting motif, and reveal that MIGA2 additionally interacts with the endoplasmic reticulum by binding to the membrane-proteins VAP-A/B. Depleting MIGA2 by CRISPR-Cas9 causes severe perturbation of triacylglycerol production during adipocyte differentiation. Specifically, our data indicate that MIGA2 is required for the de novo synthesis of lipids from non-lipid precursors. Based on its nearly ubiquitous expression pattern, we anticipate that MIGA2 is critical for lipid and energy homeostasis in a wide spectrum of cell-types.