An outer mitochondrial-membrane protein tethering mitochondria to the ER and lipid droplets
Christophe Freyre1 and Robin Klemm1,* 1Institute of Molecular Life Sciences, University of Zurich *Correspondence to Robin.Klemm@imls.uzh.ch
Lipid droplets in adipocytes are specialized in fat storage, and interact physically with mitochondria. Decades ago electron microscopy studies of differentiating adipocytes have already identified the physical association between these organelles, but the mechanism underlying the generation of this contact site and its cellular function remain largely unknown. Here, we report the discovery that a single mitochondrial outer-membrane protein tethers mitochondria to LDs. We identify a C-terminal amphipathic segment as the LD targeting motif, and find that the middle domain binds to the endoplasmic reticulum, remarkably forming a dynamic contact site between three organelles. Using CRISPR-Cas9 gene editing, we find that the knock out severely perturbs adipocyte-differentiation, which likely explains the drastic reduction of body fat in the corresponding knock-out mouse model. In contrast, inducing the expression from a trans-gene, increases differentiation efficiency and most interestingly boosts clonal expansion, a process which is also part of many other differentiation programs. Based on these findings and the presence of this contact site protein in a number of other tissues including the intestine, brain, and even oocytes, we anticipate that the described mechanism might be involved in a novel pathway of lipid and energy homeostasis in a wide spectrum of cell types.
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